US7872124B2 - Dipeptidyl peptidase inhibitors - Google Patents

Dipeptidyl peptidase inhibitors Download PDF

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US7872124B2
US7872124B2 US11/305,818 US30581805A US7872124B2 US 7872124 B2 US7872124 B2 US 7872124B2 US 30581805 A US30581805 A US 30581805A US 7872124 B2 US7872124 B2 US 7872124B2
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alkyl
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phenyl
amino
cyano
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US20060135767A1 (en
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Jun Feng
II Stephen L. Gwaltney
Jeffrey A. Stafford
Michael B. Wallace
Zhiyuan Zhang
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Takeda Pharmaceutical Co Ltd
Takeda California Inc
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61P19/00—Drugs for skeletal disorders
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds that may be used to inhibit dipeptidyl peptidases as well as compositions of matter and kits comprising these compounds.
  • the present invention also relates to methods for inhibiting dipeptidyl peptidases as well as treatment methods using compounds according to the present invention.
  • Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type II membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-IV, FAP ⁇ , adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylproly
  • DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-Gly or X-Ser has also been reported for some naturally occurring peptides.
  • DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of disease states, some of which are discussed below.
  • DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
  • GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine.
  • DPP-IV has been shown to be the primary degrading enzyme of GLP-1 (7-36) in vivo.
  • GLP-1 (7-36) is degraded by DPP-IV efficiently to GLP-1 (9-36), which has been speculated to act as a physiological antagonist to GLP-1 (7-36).
  • Inhibiting DPP-IV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-1 (7-36) and attenuating the formation of its antagonist GLP-1 (9-36).
  • DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • diabetes in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • ITT impaired glucose tolerance
  • IGF impaired fasting plasma glucose
  • metabolic acidosis ketosis
  • ketosis ketosis
  • appetite regulation and obesity are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose
  • DPP-IV expression is increased in T-cells upon mitogenic or antigenic stimulation (Mattem, T., et al., Scand. J. Immunol., 1991, 33, 737). It has been reported that inhibitors of DPP-IV and antibodies to DPP-IV suppress the proliferation of mitogen-stimulated and antigen-stimulated T-cells in a dose-dependant manner (Schon, E., et al., Biol. Chem., 1991, 372, 305). Various other functions of T-lymphocytes such as cytokine production, IL-2 mediated cell proliferation and B-cell helper activity have been shown to be dependent on DPP-IV activity (Schon, E., et al., Scand. J.
  • DPP-IV inhibitors based on boroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Sci. USA, 1991, 88, 1556) although unstable, were effective at inhibiting antigen-induced lymphocyte proliferation and IL-2 production in murine CD4+ T-helper cells.
  • Such boronic acid inhibitors have been shown to have an effect in vivo in mice causing suppression of antibody production induced by immune challenge (Kubota, T. et al., Clin. Exp. Immun., 1992, 89, 192).
  • DPP-IV The role of DPP-IV in regulating T lymphocyte activation may also be attributed, in part, to its cell-surface association with the transmembrane phosphatase, CD45. DPP-IV inhibitors or non-active site ligands may possibly disrupt the CD45-DPP-IV association.
  • CD45 is known to be an integral component of the T-cell signaling apparatus. It has been reported that DPP-IV is essential for the penetration and infectivity of HIV-1 and HIV-2 viruses in CD4+ T-cells (Wakselman, M., Nguyen, C., Mazaleyrat, J.-P., Callebaut, C., Krust, B., Hovanessian, A.
  • inhibitors of DPP-IV may be useful immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
  • lung endothelial cell DPP-IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells (Johnson, R. C., et al., J. Cell. Biol., 1993, 121, 1423). DPP-IV is known to bind to fibronectin and some metastatic tumor cells are known to carry large amounts of fibronectin on their surface. Potent DPP-IV inhibitors may be useful as drugs to prevent metastases of, for example, breast and prostrate tumors to the lungs.
  • DPP-IV inhibitors may be useful as agents to treat dermatological diseases such as psoriasis and lichen planus.
  • DPP-IV inhibitors may also act to suppress sperm motility and therefore act as a male contraceptive agent.
  • DPP-IV inhibitors have been implicated as novel for treatment of infertility, and particularly human female infertility due to Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is a condition characterized by thickening of the ovarian capsule and formation of multiple follicular cysts. It results in infertility and amenorrhea.
  • PCOS Polycystic ovary syndrome
  • DPP-IV is thought to play a role in the cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides.
  • Stimulated hematopoietic cells are useful for the treatment of disorders that are characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer. It was discovered that inhibitors of dipeptidyl peptidase type IV are useful for stimulating the growth and differentiation of hematopoietic cells in the absence of exogenously added cytokines or other growth factors or stromal cells.
  • DPP-IV in human plasma has been shown to cleave N-terminal Tyr-Ala from growth hormone-releasing factor and cause inactivation of this hormone. Therefore, inhibitors of DPP-IV may be useful in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
  • Dwarfism growth hormone deficiency
  • DPP-IV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptides substance P, neuropeptide Y and CLIP (Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV, Regul. Pept., 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U., Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes, Neuropeptides, 31, 41, 1997).
  • DPP-IV inhibitors may also be useful agents for the regulation or normalization of neurological disorders.
  • the present invention relates to compounds that have activity for inhibiting DPP-IV. It is noted that these compounds may also have activity for inhibiting other S9 proteases and thus may be used against these other S9 proteases as well as DPP-IV.
  • the present invention also provides compositions, articles of manufacture and kits comprising these compounds.
  • a pharmaceutical composition that comprises a DPP-IV inhibitor according to the present invention as an active ingredient.
  • Pharmaceutical compositions according to the invention may optionally comprise 0.001%-100% of one or more DPP-IV inhibitors of this invention.
  • These pharmaceutical compositions may be administered or coadministered by a wide variety of routes, including for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the compositions may also be administered or coadministered in slow release dosage forms.
  • the invention is also directed to kits and other articles of manufacture for treating disease states associated with DPP-IV.
  • a kit comprising a composition comprising at least one DPP-IV inhibitor of the present invention in combination with instructions.
  • the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • an article of manufacture comprises a composition comprising at least one DPP-IV inhibitor of the present invention in combination with packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • the compounds, compositions, kits and articles of manufacture are used to inhibit DPP-IV.
  • the compounds, compositions, kits and articles of manufacture are used to treat a disease state for which DPP-IV possesses activity that contributes to the pathology and/or symptomology of the disease state.
  • a compound is administered to a subject wherein DPP-IV activity within the subject is altered, preferably reduced.
  • a prodrug of a compound is administered to a subject that is converted to the compound in vivo where it inhibits DPP-IV.
  • a method of inhibiting DPP-IV comprises contacting DPP-IV with a compound according to the present invention.
  • a method of inhibiting DPP-IV comprises causing a compound according to the present invention to be present in a subject in order to inhibit DPP-IV in vivo.
  • a method of inhibiting DPP-IV comprises administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits DPP-IV in vivo.
  • the compounds of the present invention may be the first or second compounds.
  • a therapeutic method comprises administering a compound according to the present invention.
  • a method of inhibiting cell proliferation comprises contacting a cell with an effective amount of a compound according to the present invention.
  • a method of inhibiting cell proliferation in a patient comprises administering to the patient a therapeutically effective amount of a compound according to the present invention.
  • a method of treating a condition in a patient which is known to be mediated by DPP-IV, or which is known to be treated by DPP-IV inhibitors comprising administering to the patient a therapeutically effective amount of a compound according to the present invention.
  • a method for using a compound according to the present invention in order to manufacture a medicament for use in the treatment of disease state which is known to be mediated by DPP-IV, or which is known to be treated by DPP-IV inhibitors.
  • a method for treating a disease state for which DPP-IV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: causing a compound according to the present invention to be present in a subject in a therapeutically effective amount for the disease state.
  • a method for treating a disease state for which DPP-IV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a first compound to a subject that is converted in vivo to a second compound such that the second compound is present in the subject in a therapeutically effective amount for the disease state.
  • the compounds of the present invention may be the first or second compounds.
  • a method for treating a disease state for which DPP-IV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising: administering a compound according to the present invention to a subject such that the compound is present in the subject in a therapeutically effective amount for the disease state.
  • a method for treating a cell proliferative disease state comprising treating cells with a compound according to the present invention in combination with an anti-proliferative agent, wherein the cells are treated with the compound according to the present invention before, at the same time, and/or after the cells are treated with the anti-proliferative agent, referred to herein as combination therapy.
  • combination therapy is intended to cover when agents are administered before or after each other (sequential therapy) as well as when the agents are administered at the same time.
  • diabetes more particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation, obesity, immunosuppressants or
  • the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well known in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
  • prodrugs may also be administered which are altered in vivo and become a compound according to the present invention.
  • the various methods of using the compounds of the present invention are intended, regardless of whether prodrug delivery is specified, to encompass the administration of a prodrug that is converted in vivo to a compound according to the present invention.
  • certain compounds of the present invention may be altered in vivo prior to inhibiting DPP-IV and thus may themselves be prodrugs for another compound.
  • Such prodrugs of another compound may or may not themselves independently have DPP-IV inhibitory activity.
  • FIG. 1 illustrates a ribbon diagram overview of the structure of DPP-IV, highlighting the secondary structural elements of the protein.
  • FIG. 2 depicts different, non-exclusive, representative 5,6- and 6,6-membered fused ring structures that may be formed when R 2 and R 3 are taken together to form a substituted or unsubstituted ring, wherein R 23 is -LX or R 1 .
  • the rings shown in FIG. 2 are unsubstituted. It is noted that the rings may optionally be further substituted by one or more substituents.
  • Alicyclic means a moiety comprising a non-aromatic ring structure. Alicyclic moieties may be saturated or partially unsaturated with one, two or more double or triple bonds. Alicyclic moieties may also optionally comprise heteroatoms such as nitrogen, oxygen and sulfur. The nitrogen atoms can be optionally quaternerized or oxidized and the sulfur atoms can be optionally oxidized.
  • alicyclic moieties include, but are not limited to moieties with C3-C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.
  • C3-C8 rings such as cyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene, cycloheptadiene, cyclooctane, cyclooctene, and
  • “Aliphatic” means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one, two or more double or triple bonds.
  • Alkoxy means an oxygen moiety having a further alkyl substituent.
  • the alkoxy groups of the present invention can be optionally substituted.
  • Alkyl represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having a chain of carbon atoms, optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See “aminoalkyl”) between the carbon atoms.
  • oxaalkyl oxygen
  • aminoalkyl nitrogen atoms between the carbon atoms.
  • C X alkyl and C X-Y alkyl are typically used where X and Y indicate the number of carbon atoms in the chain.
  • C 1-6 alkyl includes alkyls that have a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
  • 1 and 6 carbons e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-
  • Alkyl represented along with another radical means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C 6-10 )aryl(C 1-3 )alkyl includes, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).
  • Alkylene unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical.
  • C X alkylene and C X-Y alkylene are typically used where X and Y indicate the number of carbon atoms in the chain.
  • C 1-6 alkylene includes methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), trimethylene (—CH 2 CH 2 CH 2 —), tetramethylene (—CH 2 CH 2 CH 2 CH 2 —) 2-butenylene (—CH 2 CH ⁇ CHCH 2 —), 2-methyltetramethylene (—CH 2 CH(CH 3 )CH 2 CH 2 —), pentamethylene (—CH 2 CH 2 CH 2 CH 2 CH 2 —) and the like.
  • Alkylidene means a straight or branched saturated or unsaturated, aliphatic radical connected to the parent molecule by a double bond.
  • C X alkylidene and C X-Y alkylidene are typically used where X and Y indicate the number of carbon atoms in the chain.
  • C 1-6 alkylidene includes methylene ( ⁇ CH 2 ), ethylidene ( ⁇ CHCH 3 ), isopropylidene ( ⁇ C(CH 3 ) 2 ), propylidene ( ⁇ CHCH 2 CH 3 ), allylidene ( ⁇ CH—CH ⁇ CH 2 ), and the like.
  • Amino means a nitrogen moiety having two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
  • representative amino groups include —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC 1-3 -alkyl, —N(C 1-3 -alkyl) 2 and the like.
  • the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Aminoalkyl means an alkyl, as defined above, except where one or more substituted or unsubstituted nitrogen atoms (—N—) are positioned between carbon atoms of the alkyl.
  • an (C 2-6 ) aminoalkyl refers to a chain comprising between 2 and 6 carbons and one or more nitrogen atoms positioned between the carbon atoms.
  • Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
  • non-mammals e.g., birds, and the like.
  • “Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp 2 hybridized and the total number of pi electrons is equal to 4n+2.
  • An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
  • Aryl means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl is a heteroaryl. C X aryl and C X-Y aryl are typically used where X and Y indicate the number of atoms in the ring.
  • Bicycloalkyl means a saturated or partially unsaturated fused bicyclic or bridged polycyclic ring assembly.
  • “Bicycloaryl” means a bicyclic ring assembly wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic.
  • C X bicycloaryl and C X-Y bicycloaryl are typically used where X and Y indicate the number of carbon atoms in the bicyclic ring assembly and directly attached to the ring.
  • “Bridging ring” as used herein refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where two ring atoms that are common to both rings are not directly bound to each other.
  • Non-exclusive examples of common compounds having a bridging ring include borneol, norbornane, 7-oxabicyclo[2.2.1]heptane, and the like.
  • One or both rings of the bicyclic system may also comprise heteroatoms.
  • Carbamoyl means the radical —OC(O)NR a R b where R a and R b are each independently two further substituents where a hydrogen or carbon atom is attached to the nitrogen.
  • Carbocycle means a ring consisting of carbon atoms.
  • Carbocyclic ketone derivative means a carbocyclic derivative wherein the ring contains a —CO— moiety.
  • Carbonyl means the radical —CO—. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones.
  • Carboxy means the radical —CO 2 —. It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
  • “Cyano” means the radical —CN.
  • Cycloalkyl means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly.
  • C X cycloalkyl and C X-Y cycloalkyl are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • C 3-10 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like.
  • Cycloalkylene means a divalent saturated or partially unsaturated, monocyclic or polycyclic ring assembly.
  • C X cycloalkylene and C X-Y cycloalkylene are typically used where X and Y indicate the number of carbon atoms in the ring assembly.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
  • fused ring refers to a ring that is bonded to another ring to form a compound having a bicyclic structure where the ring atoms that are common to both rings are directly bound to each other.
  • Non-exclusive examples of common fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, furan, benzofuran, quinoline, and the like.
  • Compounds having fused ring systems may be saturated, partially saturated, carbocyclics, heterocyclics, aromatics, heteroaromatics, and the like.
  • Halo means fluoro, chloro, bromo or iodo.
  • Halo-substituted alkyl as an isolated group or part of a larger group, means “alkyl” substituted by one or more “halo” atoms, as such terms are defined in this Application.
  • Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C 1-3 )alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
  • Heteroatom refers to an atom that is not a carbon atom. Particular examples of heteroatoms include, but are not limited to nitrogen, oxygen, and sulfur.
  • Heteroatom moiety includes a moiety where the atom by which the moiety is attached is not a carbon.
  • heteroatom moieties include —N ⁇ , —NR c —, —N + (O ⁇ ) ⁇ , —O—, —S— or —S(O) 2 —, wherein R c is further substituent.
  • Heterobicycloalkyl means bicycloalkyl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
  • hetero(C 9-12 )bicycloalkyl as used in this application includes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl, 2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and the like.
  • Heterocycloalkylene means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms is replaced by a heteroatom.
  • Heteroaryl means a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is a heteroatom and the remaining ring atoms are carbon.
  • the nitrogen atoms can be optionally quaternerized and the sulfur atoms can be optionally oxidized.
  • Heteroaryl groups of this invention include, but are not limited to, those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.
  • Heteroaryl also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring.
  • bicyclic or tricyclic heteroaryls include, but are not limited to, those derived from benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,5-a]pyrimidine,
  • the bicyclic or tricyclic heteroaryl rings can be attached to the parent molecule through either the heteroaryl group itself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused.
  • the heteroaryl groups of this invention can be substituted or unsubstituted.
  • Heterobicycloaryl means bicycloaryl, as defined in this Application, provided that one or more of the atoms within the ring is a heteroatom.
  • hetero(C 4-12 )bicycloaryl as used in this Application includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and the like.
  • Heterocycloalkyl means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom selected, independently from N, O, or S.
  • Non-exclusive examples of heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, 1,4-dioxanyl and the like.
  • Haldroxy means the radical —OH.
  • Iminoketone derivative means a derivative comprising the moiety —C(NR)—, wherein R comprises a hydrogen or carbon atom attached to the nitrogen.
  • “Isomers” mean any compound having an identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers.” A carbon atom bonded to four nonidentical substituents is termed a “chiral center.” A compound with one chiral center has two enantiomeric forms of opposite chirality.
  • a mixture of the two enantiomeric forms is termed a “racemic mixture.”
  • a compound that has more than one chiral center has 2 n-1 enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a “diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see “Advanced Organic Chemistry”, 4th edition, March, Jerry, John Wiley & Sons, New York, 1992).
  • Niro means the radical —NO 2 .
  • Oxaalkyl means an alkyl, as defined above, except where one or more oxygen atoms (—O—) are positioned between carbon atoms of the alkyl.
  • an (C 2-6 )oxaalkyl refers to a chain comprising between 2 and 6 carbons and one or more oxygen atoms positioned between the carbon atoms.
  • Oxoalkyl means an alkyl, further substituted with a carbonyl group.
  • the carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts of inhibitors of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention.
  • the prodrug itself may or may not also have DPP-IV inhibitory activity.
  • an inhibitor comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
  • esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
  • an inhibitor comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
  • Protected derivatives means derivatives of inhibitors in which a reactive site or sites are blocked with protecting groups. Protected derivatives are useful in the preparation of inhibitors or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
  • “Substituted or unsubstituted” means that a given moiety may consist of only hydrogen substitutents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • isopropyl is an example of an ethylene moiety that is substituted by —CH 3 .
  • a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituents include, but are not limited to, aldehyde, alicyclic, aliphatic, alkyl, alkylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted.
  • “Sulfinyl” means the radical —SO—. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
  • “Sulfonyl” means the radical —SO 2 —. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • Thiocarbonyl means the radical —CS—. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
  • Treatment or “treating” means any administration of a compound of the present invention and includes:
  • a C 1 alkyl indicates that there is one carbon atom but does not indicate what are the substituents on the carbon atom.
  • a C 1 alkyl comprises methyl (i.e., —CH 3 ) as well as —CR a R b R c where R a , R b , and R c may each independently be hydrogen or any other substituent where the atom attached to the carbon is a heteroatom or cyano.
  • CF 3 , CH 2 OH and CH 2 CN for example, are all C 1 alkyls.
  • the present invention relates to compounds, compositions, kits and articles of manufacture that may be used to inhibit dipeptidyl peptidases IV (referred to herein as DPP-IV).
  • DPP-IV (EC.3.4.14.5 also known as DPP4, DP4, DAP-IV, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp) or CD26) is a 766 residue, 240 kDa protein that is a highly specific membrane bound non-classical serine aminodipeptidase.
  • DPP-IV has a serine type mechanism of protease activity, cleaving off dipeptides from the amino-terminus of peptides with proline or alanine at the penultimate position. In addition the slow release of dipeptides of the type X-Gly or X-Ser is reported for some naturally occurring peptides.
  • DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26.
  • the wild-type form of full length DPP-IV is described in GenBank Accession Number NM — 001935 (“Dipeptidyl peptidase IV (CD 26) gene expression in enterocyte-like colon cancer cell lines HT-29 and Caco-2.
  • DPP-IV is a member of the S9 family of serine proteases, more particularly the S9B family.
  • Other members of the S9 family include, but are not limited to:
  • the compounds of the present invention may also possess inhibitory activity for other S9 family members and thus may be used to address disease states associated with these other family members.
  • FIG. 1 illustrates a ribbon diagram overview of the structure of DPP-IV, highlighting secondary structural elements of the protein.
  • DPP-IV is a cylindrical shaped molecule with an approximate height of 70 ⁇ and a diameter of 60 ⁇ .
  • the catalytic triad of DPP-IV (Ser642, Asp720 and His752) is illustrated in the center of the figure by a “ball and stick” representation. This triad of amino acids is located in the peptidase domain or catalytic domain of DPP-IV.
  • the catalytic domain is covalently linked to the ⁇ -propeller domain.
  • the catalytic domain of DPP-IV includes residues 1-67 and 511-778.
  • the catalytic domain of DPP-IV adopts a characteristic ⁇ / ⁇ hydrolase fold.
  • the core of this domain contains an 8-stranded ⁇ -sheet with all strands being parallel except one.
  • the ⁇ -sheet is significantly twisted and is flanked by three ⁇ -helices on one side and five ⁇ -helices on the other.
  • the topology of the ⁇ -strands is 1, 2, ⁇ 1 ⁇ , 2 ⁇ and (1 ⁇ ) (J. S. Richardson: The anatomy and taxonomy of protein structure; (1981) Adv. Protein Chem. 269, 15076-15084).
  • a number of residues were identified that contribute to the shape and charge characteristics of the active site. Knowledge of these residues has been an important contribution to the design of DPP-IV inhibitors of the present invention.
  • DPP-IV inhibitors of the present invention comprise the Formulae
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • Z is selected from the group consisting of halo, perhalo(C 1-10 )alkyl, amino, cyano, thio, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C -10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • L is a linker providing 0-6 atom separation between X and the ring to which L is attached;
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, or 3;
  • Z is selected from the group consisting of halo, perhalo(C 1-10 )alkyl, amino, cyano, thio, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring; and
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, 3, 4, or 5;
  • n 0, 1, 2, or 3;
  • Z is selected from the group consisting of halo, perhalo(C 1-10 )alkyl, amino, cyano, thio, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring; and
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, or 3;
  • each of T, U, V, W and Y is independently nitrogen or CR 16 , provided that no more than two of T, U, V, W and Y are nitrogen;
  • Z is selected from the group consisting of halo, perhalo(C 1-10 )alkyl, amino, cyano, thio, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, and a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring; and
  • each R 16 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • R 1 is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 4-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl(C 1-5 )alkyl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted; and
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, sulfonyl group, sulfinyl group, each substituted or unsubstituted, or R 9 and R 10 are taken together to form a 5, 6, or 7 membered ring, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 9 and R 10 are each independently hydrogen, perhalo(C 1-10 )alkyl, amino, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, sulfonyl group, sulfinyl group, each substituted or unsubstituted, or R 9 and R 10 are taken together to form a 5, 6, or 7 membered ring, each substituted or unsubstituted;
  • L is a linker providing 0-6 atom separation between X and the ring to which L is attached;
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, or 3;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfuryl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group, sulf
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
  • R 9 and R 10 are each independently hydrogen, perhalo(C 1-10 )alkyl, amino, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, sulfonyl group, sulfinyl group, each substituted or unsubstituted, or R 9 and R 10 are taken together to form a 5, 6, or 7 membered ring, each substituted or unsubstituted; and
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, 3, 4, or 5;
  • n 0, 1, 2, or 3;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; and
  • R 9 and R 10 are each independently hydrogen, perhalo(C 1-10 )alkyl, amino, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, sulfonyl group, sulfinyl group, each substituted or unsubstituted, or R 9 and R 10 are taken together to form a 5, 6, or 7 membered ring, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, or 3;
  • each of T, U, V, W, and Y is independently nitrogen or CR 16 , provided that no more than two of T, U, V, W, and Y are nitrogen;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
  • each R 16 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; and
  • R 9 and R 10 are each independently hydrogen, perhalo(C 1-10 )alkyl, amino, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, sulfonyl group, sulfinyl group, each substituted or unsubstituted, or R 9 and R 10 are taken together to form a 5, 6, or 7 membered ring, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • p 0-10
  • R 1 is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 4-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl(C 1-5 )alkyl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted; and
  • each R 22 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • p 0-10
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • each R 22 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
  • L is a linker providing 0-6 atom separation between X and the ring to which L is attached;
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, or 3;
  • p 0-10
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
  • each R 22 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; and
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, 3, 4, or 5;
  • n 0, 1, 2, or 3;
  • p 0-10
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; and
  • each R 22 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • n 0, 1, 2, or 3;
  • p 0-10
  • each of T, U, V, W, and Y is independently nitrogen or CR 16 , provided that no more than two of T, U, V, W, and Y are nitrogen;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, a substituted or unsubstituted (C 1-10 )alkyl, a substituted or unsubstituted (C 1-10 )alkoxy, cyano, and halo, or where R 5 and R 6 are taken together to form a ring;
  • each R 16 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; and
  • each R 22 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • DPP-IV inhibitors of the present invention comprise the Formulae:
  • E is CH or N
  • Q is selected from the group consisting of CO, CS, SO, SO 2 , or C ⁇ NR 4 ;
  • M is a moiety providing 1-6 atom separation between R 19 and the ring to which M is attached;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, alkenyl, alkynyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imine group,
  • R 4 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted;
  • R 19 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein
  • L is a linker providing 0-6 atom separation between X and the ring to which L is attached;
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • M provides 1-4 atom separation between R 19 and the ring. In another variation, M provides 1-3 atom separation between R 19 and the ring. In yet another variation, M is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —C(O)—, —CH 2 C(O)—, —C(O)CH 2 —, —CH 2 —C(O)CH 2 CH 2 —, —CH 2 CH 2 C(O)—, —O—, —OCH 2 —, —CH 2 O—, —CH 2 OCH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —N(CH 3 )—, —NHCH 2 —, —CH 2 NH—, —CH 2 NHCH 2 —, —NHCH 2 CH 2 —, —CH 2 CH 2 NH—
  • R 19 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein.
  • R 19 is selected from the group consisting of a primary, secondary, or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.
  • R 19 is selected from the group consisting of a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring wherein at least one substituent is selected from the group consisting of a primary, secondary, or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom.
  • the basic nitrogen of R 19 is separated from the ring atom to which M is attached by between 1-5 atoms. In yet another variation, the basic nitrogen of R 19 forms part of a primary, secondary, or tertiary amine. In another variation, R 19 is selected from the group consisting of a heterocycloalkyl comprising a nitrogen ring atom or a heteroaryl comprising a nitrogen ring atom.
  • -MR 19 is selected from the group consisting of:
  • each R 8 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that at least one R 8 includes the basic nitrogen of R 19 .
  • At least one R 8 is a primary, secondary, or tertiary amine.
  • at least one R 8 is a substituted or unsubstituted heterocycloalkyl comprising a nitrogen ring atom or a substituted or unsubstituted heteroaryl comprising a nitrogen ring atom.
  • at least one R 8 is selected from the group consisting of —NH 2 , —NH(C 1-5 alkyl), —N(C 1-5 alkyl) 2 , piperazine, imidazole, and pyridine.
  • -MR 19 is selected from the group consisting of:
  • each R 8 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted, with the proviso that at least one R 8 includes the basic nitrogen of R 19 .
  • At least one R 8 is a primary, secondary, or tertiary amine.
  • at least one R 8 is a substituted or unsubstituted heterocycloalkyl comprising a nitrogen ring atom or a substituted or unsubstituted heteroaryl comprising a nitrogen ring atom.
  • at least one R 8 is selected from the group consisting of —NH 2 , —NH(C 1-5 alkyl), —N(C 1-5 alkyl) 2 , piperazine, imidazole, and pyridine.
  • L provides 0-3 atom separation between X and the ring. In one variation, L provides 1-3 atom separation between X and the ring. In another variation, L provides 0 atom separation between X and the ring. In yet another variation, L provides 1 atom separation between X and the ring. According to another variation, the 1 atom separation is provided by an atom selected from the group consisting of C, N, O, and S. In yet another particular variation, the 1 atom separation is provided by a carbon atom. In one particular variation, the 1 atom separation is provided by an oxygen atom. In another particular variation, the 1 atom separation is provided by a nitrogen atom.
  • L is a linker providing 1, 2, or 3 atom separation between X and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen and sulfur.
  • L is a linker providing 1, 2, or 3 atom separation between X and the ring to which L is attached and the 1, 2, or 3 atoms of L providing the separation comprise carbon atoms.
  • L is a linker providing 1, 2, or 3 atom separation between X and the ring to which L is attached and the 1, 2, or 3 atoms of L providing the separation are selected from the group of linkers consisting of at least one oxygen or at least one nitrogen atom.
  • L is a carbonyl.
  • L is a linker providing 0-6 atom separation between X and the ring to which L is attached, with the proviso that, L is not —NH— or —N ⁇ CH—.
  • L is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • L is selected from the group consisting of —CH 2 —, —CHR 12 —, —C(R 12 )(R 12 )—, —C(O)—, —C(S)—, —C(NH)—, —C(NR 12 )—, —O—, —N(H)—, —N(R 12 )—, and —S— where R 12 and R 12 are each independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, cyano, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl,
  • L is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —C(O)—, —CH 2 C(O)—, —C(O)CH 2 —, —CH 2 —C(O)CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 CH 2 C(O)—, —O—, —OCH 2 —, —CH 2 O—, —CH 2 OCH 2 —, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —N(CH 3 )—, —NHCH 2 —, —CH 2 NH—, —CH 2 NHCH 2 —, —NHCH 2 CH 2 —, —CH 2 CH 2 NH—, —NH—C(O)—, —NCH 3 —C(O)—, —C(O)NH—, —C(O)—, —C
  • L is selected from the group consisting of —CH 2 —, —C(O)—, —CH 2 C(O)—, —C(O)CH 2 —, —CH 2 —C(O)CH 2 —, —C(O)CH 2 CH 2 —, and —CH 2 CH 2 C(O)—.
  • X is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 4-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substitute
  • X is selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
  • X is a substituted or unsubstituted cycloalkyl or heterocycloalkyl.
  • X is a substituted or unsubstituted (C 3-7 )cycloalkyl. In another particular variation, X is a substituted or unsubstituted (C 3-7 )heterocycloalkyl. In yet another variation, X is a substituted or unsubstituted aryl or heteroaryl. In another variation, X is a substituted or unsubstituted phenyl. According to certain variations of the above, X is a substituted or unsubstituted heteroaryl.
  • X is a ring having a non-hydrogen substituent at a 2 or 3 position of the ring.
  • X has a non-hydrogen substituent at a 2 or 3 position of the ring wherein the non-hydrogen substituent is selected from the group consisting of (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, amino, aryl, heteroaryl, hydroxy
  • X is selected from the group consisting of (2-cyano)phenyl, (3-cyano)phenyl, (2-hydroxy)phenyl, (3-hydroxy)phenyl, (2-alkenyl)phenyl, (3-alkenyl)phenyl, (2-alkynyl)phenyl, (3-alkynyl)phenyl, (2-nitro)phenyl, (3-nitro)phenyl, (2-carboxy)phenyl, (3-carboxy)phenyl, (2-carboxamido)phenyl, (3-carboxamido)phenyl, (2-sulfonamido)phenyl, (3-sulfonamido)phenyl, (2-tetrazolyl)phenyl, (3-tetrazolyl)phenyl, (2-aminomethyl)phenyl, (3-aminomethyl)phenyl, (2-amino)phenyl, (3-amino)phenyl, (2-hydroxymethyl)phenyl
  • X is selected from the group consisting of:
  • A is S, O, or NR 21 ;
  • B is CR 20 or N
  • R 20 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, thio, cyano, CF 3 , nitro, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfinyl group; and
  • R 21 is independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, cyano, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfinyl group.
  • X is selected from the group consisting of:
  • t 0, 1, 2, or 3;
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • X is selected from the group consisting of:
  • t 0, 1, 2, or 3;
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • R 7 is independently selected from the group consisting of -cyano, -methoxy, -nitro, -carboxy, -sulfonamido, -tetrazolyl, -aminomethyl, -hydroxymethyl, -phenyl, -halo, —CONH 2 , —CONH(C 1-7 )alkyl, —CO 2 (C 1-7 )alkyl, —NH 2 , —OH, —(C 1-5 )alkyl, -alkenyl, -alkynyl, —CCH, (C 1-5 )cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, each substituted or unsubstituted.
  • -LX is —OR 11 , where R 11 is selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl.
  • -LX is selected from the group consisting of —(CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(3-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(3-alkynyl)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(2-carboxy)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(2-carboxamido)phenyl,
  • -LX is selected from the group consisting of —(C 1 )alkyl-aryl, —(C 1 )alkyl-bicycloaryl, -aminoaryl, -aminoheteroaryl, -aminobicycloaryl, -aminoheterobicycloaryl, —O-aryl, —O-heteroaryl, —O-bicycloaryl, —O-heterobicycloaryl, —S-aryl, —S-heteroaryl, —S-bicycloaryl, —S-heterobicycloaryl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-bicycloaryl, —C(O)-heterobicycloaryl, —C(S)-aryl, —C(S)-heteroaryl, —C(O)-bicycloaryl, —C(
  • Z is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted.
  • Z is a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring.
  • Z is a substituted or unsubstituted 3, 4, 5, 6, or 7 membered cycloalkyl.
  • Z is a substituted or unsubstituted 4, 5, 6, or 7 membered heterocycloalkyl.
  • Z comprises O, N(O), N, S, SO, SO 2 , or a carbonyl group in the ring.
  • Z is a substituted or unsubstituted aryl.
  • Z is substituted or unsubstituted phenyl.
  • Z is a substituted or unsubstituted heteroaryl.
  • Z is —NR 9 R 10 where R 9 and R 10 together are —(CH 2 ) 46 with or without being interrupted by one O, S, SO, SO 2 , carbonyl group, N(O), NH, N-(aryl), N-(aryl(C 1-5 )alkyl), N-(carboxy(C 1-5 )alkyl), or N—(C 1-2 )alkyl) group, each substituted or unsubstituted.
  • Z is —NR 9 R 10 , where R 9 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloaryl, each substituted or unsubstituted and hetero(C 8-12 )bicycloaryl, and R 10 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-8 )alkyl.
  • Z is —NR 9 R 10 where R 9 and R 10 are taken together to form a substituted or unsubstituted 5, 6, or 7 membered heterocycloalkyl, heteroaryl, or heterobicycloaryl.
  • R 9 and R 10 are taken together to form a pyrrole, pyrazole, triazole, imidazole, benzimidazole, indole, isoindole, piperidine, piperazine, pyrrolidine, homopiperazine, azetidine, and hexahydroazepine, each substituted or unsubstituted.
  • Z is selected from the group consisting of:
  • each R 8 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • Z is selected from the group consisting of
  • each R 8 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • Z is selected from the group consisting of (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted.
  • Z is a substituted or unsubstituted heteroaryl selected from the group consisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline,
  • Z is selected from the group consisting of 3-amino-piperidin-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 2-aminoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3-aminocyclopent-1-yl, 3-aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-1-yl, 3-aminohexahydroazepin-1-yl, 3-aminocyclohex-1-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, and R-3-aminopiperidin-1-yl, each substituted or unsubstituted.
  • Z is selected from the group consisting of halo, thio, hydroxyl.
  • R 1 is selected from the group consisting of
  • A is S, O, or NR 21 ;
  • B is CR 20 or N
  • R 20 is independently selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, thio, cyano, CF 3 , nitro, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfinyl group; and
  • R 21 is independently selected from the group consisting of hydrogen, perhalo(C 1-10 )alkyl, amino, cyano, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfinyl group.
  • R 1 is selected from the group consisting of:
  • t 0, 1, 2, or 3;
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • R 1 is selected from the group consisting of:
  • t 0, 1, 2, or 3;
  • each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , —OCF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • R 5 and R 6 are taken together to form a ring.
  • at least one of R 5 and R 6 is a substituted or unsubstituted —(C 1-8 )alkyleneR 17 , wherein R 17 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 4-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloalkyl, hetero(C 9-12 )bicycloalkyl, (C 9-12 )bicycloaryl and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted.
  • At least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of (C 1-6 )alkyl, cyano, halo, nitro, halo-substituted(C 1-6 )alkyl, —NR 18 R 18 , —NR 18 C(O)OR 18 , —NR 18 C(O)NR 18 R 18 , —NR 18 C(NR 18 )NR 18 R 18 , —OR 18 , —SR 18 , —C(O)OR 18 , —C(O)NR 18 R 18 , —S(O) 2 NR 18 R 18 , —P(O)(OR 18 )OR 18 , —OP(O)(OR 18 )OR 18 , —NR 18 C(O)R 18 , —S(O)R 18 , —S(O) 2 R 18 , —(C 1-8 )alkyleneC(O)R 18 , —(C 1-6
  • At least one of R 5 and R 6 is optionally substituted by one to three radicals selected from the group consisting of —NH 2 , —NHC(NH)NH 2 , —OH, —SH, —C(O)OH and —C(O)NH 2 .
  • R 5 and R 6 are hydrogen.
  • n is 1 or 2.
  • R 5 and R 6 are hydrogen and each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , (C 1-10 )alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl,
  • R 5 and R 6 are hydrogen and two R 7 are taken together to form a substituted or unsubstituted fused or bridged ring.
  • R 5 and R 6 are hydrogen, n is 1, and R 7 is 2-cyano.
  • n is 1, 2, or 3; R 5 and R 6 are hydrogen; and each R 7 is independently selected from the group consisting of halo, perhalo(C 1-10 )alkyl, CF 3 , heteroaryl, aryloxy, heteroaryloxy, cyano, nitro, hydroxy, (C 1-10 )alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
  • R 5 and R 6 are hydrogen and R 7 is 2-cyano.
  • two R 7 are taken together to form a substituted or unsubstituted fused ring.
  • two R 7 are taken together to form a substituted or unsubstituted bridged ring.
  • n is 1 or 2;
  • Z is selected from the group consisting of alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, imino group, sulfonyl group and sulfinyl group, and a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring; and R 5 and R 6 are hydrogen.
  • Q is selected from the group consisting of CO, SO and SO 2 . Further, according to the above variations, Q is selected from the group consisting of CO and SO 2 . In one variation, Q is C ⁇ NR 4 and R 4 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted.
  • At least one of R 2 and R 3 is hydrogen. Further, according to each of the above variations, at least one of R 2 and R 3 is selected from the group consisting of —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC 1-3 -alkyl, and —N(C 1-3 -alkyl) 2 , each substituted or unsubstituted.
  • At least one of R 2 and R 3 is selected from the group consisting of hydrogen, halo, perhalo(C 1-10 )alkyl, amino, cyano, nitro, thio, (C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, aryl(C 1-10 )alkyl, heteroaryl (C 1-5 )alkyl, (C 9-12 )bicycloaryl, hetero(C 8-12 )bicycloaryl, carbonyl (C 1-3 )alkyl, thiocarbonyl (C 1-3 )alkyl, sulfonyl (C 1-3 )alkyl, sulfinyl (C 1-3 )alkyl, imino (C 1-3 )alkyl, aryl, heteroaryl, hydroxy, (C 1-10 )alkoxy, aryloxy, heteroaryloxy, alkenyl, alkyny
  • At least one of R 2 and R 3 is selected from the group consisting of a (C 2-10 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy carbonyl (C 2-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy thiocarbonyl (C 2-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy sulfonyl (C 2-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy sulfinyl (C 2-3 )alkenyl; an amino, (C 1-10 )alkyl, or alkoxy imino (C 2-3 )alkenyl; an aryl (C 2-5 )alkenyl; and a heteroaryl (C 2-5 ) alkenyl, each substituted or unsubstituted.
  • a (C 2-10 )alkenyl an amino, (C 1
  • At least one of R 2 and R 3 is selected from the group consisting of a (C 2-10 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy carbonyl (C 2-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy thiocarbonyl (C 2-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy sulfonyl (C 2-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy sulfinyl (C 2-3 )alkynyl; an amino, (C 1-10 )alkyl, or alkoxy imino (C 2-3 )alkynyl; an aryl (C 2-5 ) alkynyl; and heteroaryl (C 2-5 )alkynyl, each substituted or unsubstituted.
  • At least one of R 2 and R 3 is substituted or unsubstituted (C 3-7 )cycloalkyl. In another variation, at least one of R 2 and R 3 is substituted or unsubstituted (C 3-7 )heterocycloalkyl. In another variation, at least one of R 2 and R 3 is substituted or unsubstituted aryl; or wherein at least one of R 2 and R 3 is substituted or unsubstituted phenyl.
  • At least one of R 2 and R 3 is selected from the group consisting of 2-fluorophenyl, 4-fluorostyryl, 2-methoxyphenyl, pyrrolidin-1-yl, imidazolyl, and 3-furanyl, each substituted or unsubstituted.
  • at least one of R 2 and R 3 is substituted or unsubstituted heteroaryl.
  • R 2 and R 3 is selected from the group consisting of hydrogen, cyano, —CF 3 , or hydroxy. In another variation, at least one of R 2 and R 3 is selected from the group consisting of I, Br, Cl, and F. In yet another variation of the above, at least one of R 2 and R 3 is —OR 13 where R 13 is selected from the group consisting of (C 1-10 )alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-10 )alkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted. In another variation, at least one of R 2 and R 3 is a carbonyl group. Further, in another variation, at least one of R 2 and R 3 is selected from the group consisting of an aldehyde, acid, amide, and ester.
  • At least one of R 2 and R 3 is selected from the group consisting of pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, and morpholin-4-ylcarbonyl, each substituted or unsubstituted.
  • at least one of R 2 and R 3 is selected from the group consisting of —SH, —SCH 3 , and —S(C 1-3 )alkyl, each substituted or unsubstituted.
  • R 2 and R 3 is —NR 14 R 15 where R 14 is selected from the group consisting of (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 6-12 )aryl, hetero(C 5-12 )aryl, (C 9-12 )bicycloaryl and hetero(C 8-12 )bicycloaryl, each substituted or unsubstituted, and R 15 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-8 )alkyl, and where R 14 and R 15 together are —(CH 2 ) 4-5 — optionally interrupted by one O, S, NH, or —N(C 1-3 )alkyl group, unsubstituted or substituted.
  • At least one of R 2 and R 3 is selected from the group consisting of a (C 1-3 )alkyl; an amino, (C 1-10 )alkyl, or alkoxy carbonyl (C 1-3 )alkyl; an amino, (C 1-10 )alkyl, or alkoxy thiocarbonyl (C 1-3 )alkyl; an amino, (C 1-10 )alkyl, or alkoxy sulfonyl (C 1-3 )alkyl; an amino, (C 1-10 )alkyl, or alkoxy sulfinyl (C 1-3 )alkyl; an amino, (C 1-10 )alkyl, or alkoxy imino (C 1-3 )alkyl; an aryl (C 1-5 )alkyl; and a heteroaryl (C 1-5 )alkyl, each unsubstituted or substituted.
  • At least one of R 2 and R 3 is selected from the group consisting of 1,2-dihydro-2-oxo-pyridinyl-, 1,4-dihydro-4-oxo-pyridinyl-, 2,3-dihydro-3-oxo-pyridazinyl-, 1,2,3,6-tetrahydro-3,6-dioxo-pyridazinyl-, 1,2-dihydro-2-oxo-pyrimidinyl-, 3,4-dihydro-4-oxo-pyrimidinyl-, 1,2,3,4-tetrahydro-2,4-dioxo-pyrimidinyl-, 1,2-dihydro-2-oxo-pyrazinyl, 1,2,3,4-tetrahydro-2,3-dioxo-pyrazinyl-, 2,3-dihydro-2-oxo-indolyl-, 2,3-dihydro
  • R 2 and R 3 are not hydrogen. In another variation, both R 2 and R 3 are not hydrogen.
  • R 2 is selected from the group consisting of 2-fluorophenyl, styryl, 4-fluorostyryl, 2-methoxyphenyl, pyrrolidin-1-yl, imidazolyl, and 3-furanyl each unsubstituted or substituted
  • R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, and aryl, each unsubstituted or substituted.
  • R 2 is selected from the group consisting of hydrogen, carboxyl, cyano, nitro, bromo, fluoro, chloro, iodo, —CF 3 , —CH 3 and hydroxy
  • R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, and aryl, each unsubstituted or substituted.
  • R 2 is selected from the group consisting of hydrogen, carboxyl, cyano, nitro, bromo, fluoro, chloro, iodo, —CF 3 , —CH 3 and hydroxy
  • R 3 is selected from the group consisting of hydrogen, (C 3-7 )cycloalkyl and aryl, each unsubstituted or substituted.
  • FIG. 2 depicts representative, non-limiting examples of 5,6- and 6,6-membered fused rings that may be formed when R 2 and R 3 are taken together to form a substituted or unsubstituted 5- or 6-membered fused ring, wherein R 23 is -LX or R 1 .
  • the rings shown in FIG. 2 are unsubstituted. It is noted, however, that each of these rings may be further substituted. Non-limiting examples of how these rings may be further substituted is provided by way of the particular compounds according to the present invention exemplified herein.
  • R 2 or R 3 is selected from the group consisting of —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC 1-3 -alkyl, and —N(C 1-3 -alkyl) 2 , each unsubstituted or substituted; and Z is selected from the group consisting of 3-amino-piperidin-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 2-aminoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3-aminocyclopentyl, 3-aminomethylcyclopentyl, 3-aminomethylcyclohexyl, 3-aminohexahydroazepin-1-yl, 3-aminocyclohexyl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, piperazin-1
  • Q is CO; and R 1 is selected from the group consisting of —(CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(2-methoxy)phenyl, —(CH 2 )-(3-methoxy)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(2-carboxamido)phenyl, —(CH 2 )-(3-carboxamido
  • Q is CO; and Z is selected from the group consisting of 3-amino-piperidin-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 2-aminoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3-aminocyclopentyl, 3-aminomethylcyclopentyl, 3-aminomethylcyclohexyl, 3-aminohexahydroazepin-1-yl, 3-amino-cyclohexyl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, and R-3-aminopiperidin-1-yl, each unsubstituted or substituted.
  • Q is SO; and R 1 is selected from the group consisting of —(CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(2-methoxy)phenyl, —(CH 2 )-(3-methoxy)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(2-carboxy)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(3-carboxamido)phenyl
  • Q is SO; and Z is selected from the group consisting of 3-amino-piperidin-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 2-aminoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3-aminocyclopent-1-yl, 3-aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-1-yl, 3-aminohexahydroazepin-1-yl, 3-amino-cyclohex-1-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, and R-3-aminopiperidin-1-yl, each unsubstituted or substituted.
  • Q is SO 2 ; and R 1 is selected from the group consisting of CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(2-methoxy)phenyl, —(CH 2 )-(3-methoxy)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(2-carboxy)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(3-carboxamido)phenyl, —
  • Q is SO 2 ; and Z is selected from the group consisting of 3-amino-piperidin-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 2-aminoazetidin-1-yl, 3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3-aminocyclopent-1-yl, 3-aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-1-yl, 3-aminohexahydroazepin-1-yl, 3-amino-cyclohex-1-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, and R-3-aminopiperidin-1-yl, each unsubstituted or substituted.
  • Q is CO; -L-X together are selected from the group consisting of —(CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(2-methoxy)phenyl, —(CH 2 )-(3-methoxy)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(2-carboxy)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(3-carboxamido)phen
  • Q is SO; -L-X together are selected from the group consisting of —(CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(2-methoxy)phenyl, —(CH 2 )-(3-methoxy)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(2-carboxy)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(3-carboxamido)phenyl,
  • Q is SO 2 ; -L-X together are selected from the group consisting of —(CH 2 )-(2-cyano)phenyl, —(CH 2 )-(3-cyano)phenyl, —(CH 2 )-(2-hydroxy)phenyl, —(CH 2 )-(3-hydroxy)phenyl, —(CH 2 )-(2-alkenyl)phenyl, —(CH 2 )-(2-alkynyl)phenyl, —(CH 2 )-(2-methoxy)phenyl, —(CH 2 )-(3-methoxy)phenyl, —(CH 2 )-(2-nitro)phenyl, —(CH 2 )-(3-nitro)phenyl, —(CH 2 )-(2-carboxy)phenyl, —(CH 2 )-(3-carboxy)phenyl, —(CH 2 )-(3-carboxamido)
  • DPP-IV inhibitors include, but are not limited to:
  • the present invention provides the compound in the form of a pharmaceutically acceptable salt.
  • the compound is present in a mixture of stereoisomers.
  • the compound comprises a single stereoisomer.
  • composition comprising a compound according to the above variations as an active ingredient.
  • the composition is a solid formulation adapted for oral administration.
  • the composition is a tablet.
  • the composition is a liquid formulation adapted for oral administration.
  • the composition is a liquid formulation adapted for parenteral administration.
  • the pharmaceutical composition comprising the compound according to the above variations, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, and intrathecally.
  • kits comprising the compound according to the above variation and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.
  • the kit comprises the compound in a multiple dose form.
  • an article of manufacture comprising the compound according to the above variations and packaging materials.
  • the packaging material comprises a container for housing the compound.
  • the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the article of manufacture comprises the compound in a multiple dose form.
  • a method of inhibiting DPP-IV comprising contacting DPP-IV with the compound according to the above variations.
  • a method of inhibiting DPP-IV comprising causing the compound according to any one of the above variations to be present in a subject in order to inhibit DPP-IV in vivo.
  • the method of inhibiting DPP-IV comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits DPP-IV in vivo, the second compound being the compound according to any one of the above variations.
  • a therapeutic method comprising administering the compound according to the above variations to a subject.
  • a method of treating a disease state for which DPP-IV possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing the compound according to the above variations to be present in a subject in a therapeutically effective amount for the disease state.
  • a method of treating diabetes in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the compound according to any one of the above variations and embodiments.
  • a method according to the above variation wherein the diabetes being treated is type I or type II diabetes.
  • a method of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the compound according to any one of the above variation.
  • the cancer being treated is colorectal, prostate, breast, thyroid, skin, lung, or head and neck.
  • a method of treating an autoimmune disorder in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the compound according to any one of the above variations.
  • the method wherein the autoimmune disorder being treated is selected from the group consiting of rheumatoid arthritis, psoriasis, and multiple sclerosis.
  • a method of treating a condition characterized by inadequate lymphocyte or hemapoietic cell activation or concentration in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the compound according to any one of the above variations and embodiments.
  • the condition being treated is a side effect of chemotherapy or radiation therapy.
  • the condition being treated is a result of kidney failure.
  • there is provided the above method wherein the condition being treated is a result of a bone marrow disorder.
  • a method of treating HIV infection in a patient in need thereof comprising administering to said patient a therapeutically effective amount of the compound according to any one of the above variations and embodiments.
  • the present invention provides a method of treating a condition characterized by immunodeficiency symptoms in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to the present invention.
  • the compounds of the present invention may be present and optionally administered in the form of salts, hydrates and prodrugs that are converted in vivo into the compounds of the present invention.
  • the compounds of the present invention possess a free base form
  • the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • a pharmaceutically acceptable inorganic or organic acid e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids and their corresponding salts such as sulfate, n
  • Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, byturate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, man
  • a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • bases include alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g. potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine.
  • aluminium salts of the compounds of the present invention are also included.
  • Organic base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
  • Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N
  • Compounds of the present invention that comprise basic nitrogen-containing groups may be quaternized with such agents as (C 1-4 )alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di (C 1-4 )alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; (C 10-18 )alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C 1-4 )alkyl halides, e.g., benzyl chloride and phenethyl bromide.
  • Such salts permit the preparation of both water-soluble and oil-soluble compounds of the present invention.
  • N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0° C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
  • Prodrug derivatives of compounds according to the present invention can be prepared by modifying substituents of compounds of the present invention that are then converted in vivo to a different substituent. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention.
  • prodrugs can be prepared by reacting a compound with a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods of making prodrugs are described in Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters , Vol. 4, p. 1985.
  • Protected derivatives of compounds of the present invention can also be made. Examples of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, Inc. 1999.
  • Hydrates of compounds of the present invention may also be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • a “pharmaceutically acceptable salt”, as used herein, is intended to encompass any compound according to the present invention that is utilized in the form of a salt thereof, especially where the salt confers on the compound improved pharmacokinetic properties as compared to the free form of compound or a different salt form of the compound.
  • the pharmaceutically acceptable salt form may also initially confer desirable pharmacokinetic properties on the compound that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
  • An example of a pharmacokinetic property that may be favorably affected is the manner in which the compound is transported across cell membranes, which in turn may directly and positively affect the absorption, distribution, biotransformation and excretion of the compound.
  • the solubility of the compound is usually dependent upon the character of the particular salt form thereof, which it utilized.
  • an aqueous solution of the compound will provide the most rapid absorption of the compound into the body of a subject being treated, while lipid solutions and suspensions, as well as solid dosage forms, will result in less rapid adsorption of the compound.
  • DPP-IV is believed to contribute to the pathology and/or symptomology of several different diseases such that reduction of the activity of DPP-IV in a subject through inhibition may be used to therapeutically address these disease states.
  • Examples of various diseases that may be treated using the DPP-IV inhibitors of the present invention are described herein. It is noted that additional diseases beyond those disclosed herein may be later identified as the biological roles that DPP-IV plays in various pathways becomes more fully understood.
  • DPP-IV inhibitors of the present invention may be used to treat are those involving the prevention and treatment of diabetes and obesity, in particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • type 2 diabetes mellitus in particular type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • ITT impaired glucose tolerance
  • IGF impaired fasting plasma glucose
  • metabolic acidosis ketosis
  • ketosis ketosis
  • DPP-IV inhibitors of the present invention may also be used as immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
  • immunosuppressants or cytokine release suppressant drugs
  • DPP-IV inhibitors of the present invention may also be used for treating various cancers including breast cancer, lung cancer and prostate cancer.
  • DPP-IV inhibitors of the present invention may also be used to treat dermatological diseases such as psoriasis, rheumatoid arthritis (RA) and lichen planus.
  • dermatological diseases such as psoriasis, rheumatoid arthritis (RA) and lichen planus.
  • DPP-IV inhibitors of the present invention may also be used to treat infertility and amenorrhea.
  • DPP-IV inhibitors of the present invention may also be used to modulate cleavage of various cytokines (stimulating hematopoietic cells), growth factors and neuropeptides. For example, such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer.
  • DPP-IV inhibitors of the present invention may also be used prevent or reduce cleavage of N-terminal Tyr-Ala from growth hormone-releasing factor. Accordingly, these inhibitors may be used in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
  • Dwarfism growth hormone deficiency
  • DPP-IV inhibitors of the present invention may also be used to address disease states associated with cleavage of neuropeptides and thus may be useful for the regulation or normalization of neurological disorders.
  • DPP-IV inhibitors of the present invention may be used in conjunction with other agents to inhibit undesirable and uncontrolled cell proliferation.
  • examples of other anti-cell proliferation agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATINTM protein, ENDOSTATINTM protein, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel, platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs (1-azetidine-2-
  • anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2.
  • bFGF vascular endothelial growth factor
  • FGF-5 vascular endothelial growth factor
  • VEGF isoforms VEGF-C
  • HGF/SF Ang-1/Ang-2.
  • compositions Comprising DPP-IV Inhibitors
  • compositions and administration methods may be used in conjunction with the DPP-IV inhibitors of the present invention.
  • Such compositions may include, in addition to the DPP-IV inhibitors of the present invention, conventional pharmaceutical excipients, and other conventional, pharmaceutically inactive agents.
  • the compositions may include active agents in addition to the DPP-IV inhibitors of the present invention.
  • These additional active agents may include additional compounds according to the invention, and/or one or more other pharmaceutically active agents.
  • compositions may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used.
  • routes of administration for oral administration, capsules and tablets are typically used.
  • parenteral administration reconstitution of a lyophilized powder, prepared as described herein, is typically used.
  • compositions comprising DPP-IV inhibitors of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the compounds and/or compositions according to the invention may also be administered or coadministered in slow release dosage forms.
  • the DPP-IV inhibitors and compositions comprising them may be administered or coadministered in any conventional dosage form.
  • Co-administration in the context of this invention is intended to mean the administration of more than one therapeutic agent, one of which includes a DPP-IV inhibitor, in the course of a coordinated treatment to achieve an improved clinical outcome.
  • Such co-administration may also be coextensive, that is, occurring during overlapping periods of time.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may optionally include one or more of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; agents for the adjustment of tonicity such as sodium chloride or dextrose, and agents for adjusting the acidity or alkalinity of the composition, such as alkaline or acidifying agents or buffers like carbonates, bicarbonates, phosphates, hydrochloric acid, and organic acids like acetic and citric acid.
  • Parenteral preparations may optionally be enclosed in ampules,
  • DPP-IV inhibitors according to the present invention exhibit insufficient solubility
  • methods for solubilizing the compounds include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN, or dissolution in aqueous sodium bicarbonate.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as TWEEN
  • dissolution in aqueous sodium bicarbonate aqueous sodium bicarbonate
  • Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • a solution, suspension, emulsion or the like may be formed.
  • the form of the resulting composition will depend upon a number of factors, including the intended mode of administration, and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration needed to ameliorate the disease being treated may be empirically determined.
  • compositions according to the present invention are optionally provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, dry powders for inhalers, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds, particularly the pharmaceutically acceptable salts, preferably the sodium salts, thereof.
  • the pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art.
  • Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
  • unit-dose forms include ampoules and syringes individually packaged tablet or capsule.
  • Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form.
  • Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pint or gallons.
  • multiple dose form is a multiple of unit-doses that are not segregated in packaging.
  • the composition may comprise: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polyinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polyinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • composition or formulation to be administered will, in any event, contain a sufficient quantity of a DPP-IV inhibitor of the present invention to reduce DPP-IV activity in vivo, thereby treating the disease state of the subject.
  • Dosage forms or compositions may optionally comprise one or more DPP-IV inhibitors according to the present invention in the range of 0.005% to 100% (weight/weight) with the balance comprising additional substances such as those described herein.
  • a pharmaceutically acceptable composition may optionally comprise any one or more commonly employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum.
  • compositions include solutions, suspensions, tablets, capsules, powders, dry powders for inhalers and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these formulations are known to those skilled in the art.
  • the compositions may optionally contain 0.01%-100% (weight/weight) of one or more DPP-IV inhibitors, optionally 0.1-95%, and optionally 1-95%.
  • Salts, preferably sodium salts, of the DPP-IV inhibitors may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
  • the formulations may further include other active compounds to obtain desired combinations of properties.
  • Oral pharmaceutical dosage forms may be as a solid, gel or liquid.
  • solid dosage forms include, but are not limited to tablets, capsules, granules, and bulk powders. More specific examples of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated or film-coated.
  • capsules include hard or soft gelatin capsules. Granules and powders may be provided in non-effervescent or effervescent forms. Each may be combined with other ingredients known to those skilled in the art.
  • DPP-IV inhibitors according to the present invention are provided as solid dosage forms, preferably capsules or tablets.
  • the tablets, pills, capsules, troches and the like may optionally contain one or more of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
  • binders examples include, but are not limited to, microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
  • lubricants examples include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • diluents examples include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • glidants examples include, but are not limited to, colloidal silicon dioxide.
  • disintegrating agents examples include, but are not limited to, crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • coloring agents examples include, but are not limited to, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • sweetening agents examples include, but are not limited to, sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray-dried flavors.
  • flavoring agents examples include, but are not limited to, natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
  • wetting agents examples include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • anti-emetic coatings examples include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • film coatings examples include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the salt of the compound may optionally be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • dosage unit form When the dosage unit form is a capsule, it may optionally additionally comprise a liquid carrier such as a fatty oil.
  • dosage unit forms may optionally additionally comprise various other materials that modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • Compounds according to the present invention may also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
  • a syrup may optionally comprise, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the DPP-IV inhibitors of the present invention may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
  • active materials such as antacids, H2 blockers, and diuretics.
  • Examples of pharmaceutically acceptable carriers that may be included in tablets comprising DPP-IV inhibitors of the present invention include, but are not limited to binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
  • Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
  • Sugar-coated tablets may be compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
  • Film-coated tablets may be compressed tablets that have been coated with polymers or other suitable coating. Multiple compressed tablets may be compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned.
  • Coloring agents may also be used in tablets. Flavoring and sweetening agents may be used in tablets, and are especially useful in the formation of chewable tablets and lozenges.
  • liquid oral dosage forms examples include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • aqueous solutions examples include, but are not limited to, elixirs and syrups.
  • elixirs refer to clear, sweetened, hydroalcoholic preparations.
  • pharmaceutically acceptable carriers examples include, but are not limited to solvents.
  • solvents Particular examples include glycerin, sorbitol, ethyl alcohol and syrup.
  • syrups refer to concentrated aqueous solutions of a sugar, for example, sucrose. Syrups may optionally further comprise a preservative.
  • Emulsions refer to two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. Emulsions may optionally be oil-in-water or water-in-oil emulsions. Examples of pharmaceutically acceptable carriers that may be used in emulsions include, but are not limited to non-aqueous liquids, emulsifying agents and preservatives.
  • Examples of pharmaceutically acceptable substances that may be used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents.
  • Examples of pharmaceutically acceptable substances that may be used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents may optionally be used in all of the above dosage forms.
  • preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Diluents include lactose and sucrose.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
  • wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • organic acids that may be used include citric and tartaric acid.
  • Sources of carbon dioxide that may be used in effervescent compositions include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds that produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the solution e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Other useful formulations include those set forth in U.S. Pat. Nos. Re 28,819 and 4,358,603.
  • the present invention is also directed to compositions designed to administer the DPP-IV inhibitors of the present invention by parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • injectables may be prepared in any conventional form, for example as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • excipients examples include, but are not limited to water, saline, dextrose, glycerol or ethanol.
  • the injectable compositions may also optionally comprise minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Implantation of a slow-release or sustained-release system such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplated herein.
  • the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
  • Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations.
  • Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
  • the solutions may be either aqueous or nonaqueous.
  • suitable carriers include, but are not limited to physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • Examples of pharmaceutically acceptable carriers that may optionally be used in parenteral preparations include, but are not limited to aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • nonaqueous parenteral vehicles examples include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations may be added to parenteral preparations, particularly when the preparations are packaged in multiple-dose containers and thus designed to be stored and multiple aliquots to be removed.
  • antimicrobial agents include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Examples of isotonic agents that may be used include sodium chloride and dextrose.
  • Examples of buffers that may be used include phosphate and citrate.
  • antioxidants that may be used include sodium bisulfate.
  • Examples of local anesthetics that may be used include procaine hydrochloride.
  • Examples of suspending and dispersing agents that may be used include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
  • Examples of emulsifying agents that may be used include Polysorbate 80 (TWEEN 80).
  • a sequestering or chelating agent of metal ions include EDTA.
  • Pharmaceutical carriers may also optionally include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • concentration of a DPP-IV inhibitor in the parenteral formulation may be adjusted so that an injection administers a pharmaceutically effective amount sufficient to produce the desired pharmacological effect.
  • concentration of a DPP-IV inhibitor and/or dosage to be used will ultimately depend on the age, weight and condition of the patient or animal as is known in the art.
  • Unit-dose parenteral preparations may be packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration should be sterile, as is know and practiced in the art.
  • Injectables may be designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, preferably more than 1% w/w of the DPP-IV inhibitor to the treated tissue(s).
  • the DPP-IV inhibitor may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment will be a function of the location of where the composition is parenterally administered, the carrier and other variables that may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated.
  • the DPP-IV inhibitor may optionally be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease state and may be empirically determined.
  • the DPP-IV inhibitors of the present invention may also be prepared as lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures.
  • the lyophilized powders may also be formulated as solids or gels.
  • Sterile, lyophilized powder may be prepared by dissolving the compound in a sodium phosphate buffer solution containing dextrose or other suitable excipient. Subsequent sterile filtration of the solution followed by lyophilization, under standard conditions known to those of skill in the art provides the desired formulation.
  • the lyophilized powder may optionally be prepared by dissolving dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent, about 1-20%, preferably about 5 to 15%, in a suitable buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • a DPP-IV inhibitor is added to the resulting mixture, preferably above room temperature, more preferably at about 30-35° C., and stirred until it dissolves.
  • the resulting mixture is diluted by adding more buffer to a desired concentration.
  • the resulting mixture is sterile filtered or treated to remove particulates and to insure sterility, and apportioned into vials for lyophilization. Each vial may contain a single dosage or multiple dosages of the DPP-IV inhibitor.
  • the DPP-IV inhibitors of the present invention may also be administered as topical mixtures.
  • Topical mixtures may be used for local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • the DPP-IV inhibitors may be formulated as aerosols for topical application, such as by inhalation (see, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma).
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will typically have diameters of less than 50 microns, preferably less than 10 microns.
  • the DPP-IV inhibitors may also be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the DPP-IV inhibitor alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • rectal administration may also be used.
  • pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect.
  • Rectal suppositories are used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
  • bases examples include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used.
  • Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration may be manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration.
  • oral, intravenous and tablet formulations that may optionally be used with compounds of the present invention. It is noted that these formulations may be varied depending on the particular compound being used and the indication for which the formulation is going to be used.
  • the invention is also directed to kits and other articles of manufacture for treating diseases associated with DPP-IV. It is noted that diseases are intended to cover all conditions for which the DPP-IV possesses activity that contributes to the pathology and/or symptomology of the condition.
  • a kit comprising a composition comprising at least one DPP-IV inhibitor of the present invention in combination with instructions.
  • the instructions may indicate the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • an article of manufacture comprises a composition comprising at least one DPP-IV inhibitor of the present invention in combination with packaging materials.
  • the packaging material may comprise a container for housing the composition.
  • the container may optionally comprise a label indicating the disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also optionally comprise additional components, such as syringes for administration of the composition.
  • the kit may comprise the composition in single or multiple dose forms.
  • the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container that is employed will depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension.
  • kits can be used together in a single package to market a single dosage form.
  • tablets may be contained in a bottle that is in turn contained within a box.
  • the kit includes directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, topical, transdermal and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • kits are a dispenser designed to dispense the daily doses one at a time in the order of their intended use.
  • the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen.
  • a memory-aid is a mechanical counter that indicates the number of daily doses that has been dispensed.
  • a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
  • a racemic mixture of a compound may be reacted with an optically active resolving agent to form a pair of diastereoisomeric compounds.
  • the diastereomers may then be separated in order to recover the optically pure enantiomers.
  • Dissociable complexes may also be used to resolve enantiomers (e.g., crystalline diastereoisomeric salts).
  • Diastereomers typically have sufficiently distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) that they can be readily separated by taking advantage of these dissimilarities.
  • diastereomers can typically be separated by chromatography or by separation/resolution techniques based upon differences in solubility.
  • separation/resolution techniques A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • Compounds according to the present invention can also be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds are set forth in the definitions section of this Application.
  • the salt forms of the compounds can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a compound in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • N-oxides of compounds according to the present invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0° C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the N-oxides of the compounds can be prepared from the N-oxide of an appropriate starting material.
  • Compounds in an unoxidized form can be prepared from N-oxides of compounds by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80° C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters , Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, Inc. 1999.
  • Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds according to the present invention can also be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • MS mass spectra
  • compound purity data were acquired on a Waters ZQ LC/MS single quadrupole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD).
  • ESI electrospray ionization
  • UV detector (220 and 254 nm
  • ELSD evaporative light scattering detector
  • Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230400 mesh, Merck).
  • DPP-IV inhibitors according to the present invention may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided herein in the examples. Other reaction schemes could be readily devised by those skilled in the art.
  • DPP-IV inhibitors By varying compound of general structures 1a, ArCH 2 —NH 2 (1b) and R 2 NH shown above in this example, a wide variety of different DPP-IV inhibitors according to the present invention may be synthesized.
  • various coupling agents known in the art for coupling or condensing the acid 1a and amine 1b may be employed.
  • Deprotection of the protecting group (PG) may be accomplished using various methods known in the art, for example, as referenced in T. W. Greene, cited above.
  • the cyclization reaction may be performed, for example using CDI and heat, or using other reagents known in the art.
  • Formation of the enamine 1e may be accomplished using a catalyst, such as a palladium catalyst.
  • DPP-IV inhibitors By varying the structure of compounds 2a, 2b, 2c and R 2 NH shown above in this example, a wide variety of different DPP-IV inhibitors according to the present invention may be synthesized. In addition, by varying the nature of the starting compound 2a in the above scheme, a large number of different DPP-IV inhibitors may be prepared. In the above process, the cyclization reaction may be performed, for example using heat, or using other reagents known in the art. Formation of the enamine 2e may be accomplished using a catalyst, such as a palladium catalyst.
  • DPP-IV inhibitors according to the present invention may be synthesized.
  • the nature of the starting compound 3a in the above scheme a large number of different DPP-IV inhibitors may be prepared.
  • the cyclization reaction may be performed, for example using heat, or using other reagents known in the art. Formation of the enamine 3e may be accomplished using a catalyst, such as a palladium catalyst.
  • protease inhibitory activities of DPP-IV inhibitors can be readily determined by methods known to those of ordinary skill in the art since suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Examples of assays that may be used for measuring protease inhibitory activity and selectivity are set forth below.
  • test compounds in varying concentrations ( ⁇ 10 mM final concentration) were prepared in dimethyl sulfoxide (DMSO) and then diluted into assay buffer comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and 0.1 mg/mL BSA.
  • DMSO dimethyl sulfoxide
  • Human DPP-IV (0.1 nM final concentration) is added to the dilutions and pre-incubated for 10 minutes at ambient temperature before the reaction was initiated with A-P-7-amido-4-trifluoromethylcoumarin (AP-AFC; 10 ⁇ M final concentration).
  • the total volume of the reaction mixture is 10-100 ⁇ L depending on assay formats used (384 or 96 well plates).
  • test compounds in varying concentrations ( ⁇ 10 mM final concentration) are prepared in dimethyl sulfoxide (DMSO) and then diluted into assay buffer comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and 0.1 mg/mL BSA.
  • Human FAP ⁇ (2 nM final concentration) is added to the dilutions and pre-incubated for 10 minutes at ambient temperature before the reaction is initiated with A-P-7-amido-4-trifluoromethylcoumarin (AP-AFC; 40 ⁇ M final concentration).
  • the total volume of the reaction mixture is 10-100 ⁇ L depending on assay formats used (384 or 96 well plates).
  • test compounds in varying concentrations ( ⁇ 10 mM final concentration) are prepared in dimethyl sulfoxide (DMSO) and then diluted into assay buffer comprising: 20 mM sodium phosphate, pH 7.4; 0.5 mM EDTA; 0.5 mM DTT; and 0.1 mg/mL BSA.
  • PREP EC3.4.21.26 from Flavobacterium meningosepticum; 0.2 nM final concentration
  • the PREP and compound are pre-incubated for 10 minutes at ambient temperature before the reaction was initiated with Z-G-P-AMC (10 ⁇ M final concentration).
  • the total volume of the reaction mixture is 10-100 ⁇ L depending on assay formats used (384 or 96 well plates).
  • DMSO dimethyl sulfoxide
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090275750A1 (en) * 2005-09-16 2009-11-05 Jun Feng Dipeptidyl peptidase inhibitors
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US10633382B2 (en) 2016-10-18 2020-04-28 H. Lundbeck A/S Imidazopyrazinones, pyrazolopyrimidinones and pyrazolopyridinones as PDE1 inhibitors
US10858362B2 (en) 2015-04-30 2020-12-08 H. Lundbeck A/S Imidazopyrazinones as PDE1 inhibitors
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Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087053A2 (en) 2003-03-25 2004-10-14 Syrrx, Inc. Dipeptidyl peptidase inhibitors
EP1506967B1 (en) 2003-08-13 2007-11-21 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
JP2007505121A (ja) 2003-09-08 2007-03-08 武田薬品工業株式会社 ジペプチジルぺプチダーゼ阻害剤
WO2005095381A1 (en) 2004-03-15 2005-10-13 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
DOP2006000008A (es) 2005-01-10 2006-08-31 Arena Pharm Inc Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1
TW200800213A (en) * 2005-09-02 2008-01-01 Abbott Lab Novel imidazo based heterocycles
EP1942898B2 (en) 2005-09-14 2014-05-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors for treating diabetes
PE20071221A1 (es) * 2006-04-11 2007-12-14 Arena Pharm Inc Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas
EP2402750A1 (en) * 2006-04-11 2012-01-04 Arena Pharmaceuticals, Inc. Methods of using GPR119 receptor to identify compounds useful for increasing bone mass in an individual
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8278345B2 (en) 2006-11-09 2012-10-02 Probiodrug Ag Inhibitors of glutaminyl cyclase
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
SI2091948T1 (sl) 2006-11-30 2012-07-31 Probiodrug Ag Novi inhibitorji glutaminil ciklaze
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
CN101652069A (zh) * 2007-03-27 2010-02-17 艾博特公司 新的基于咪唑并的杂环化合物
EP2865670B1 (en) 2007-04-18 2017-01-11 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
EP2108960A1 (en) * 2008-04-07 2009-10-14 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditons modulated by PYY
WO2009130232A1 (en) * 2008-04-24 2009-10-29 Glaxo Group Limited Pyrazolo [1, 5 -a] pyrazine derivatives as antagonists of v1b receptors
PL2475428T3 (pl) 2009-09-11 2015-12-31 Probiodrug Ag Pochodne heterocykliczne jako inhibitory cyklazy glutaminowej
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EP2542549B1 (en) 2010-03-03 2016-05-11 Probiodrug AG Inhibitors of glutaminyl cyclase
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WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US8907086B2 (en) 2011-03-03 2014-12-09 Merck Sharp & Dohme Corp. Fused bicyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
US8530670B2 (en) 2011-03-16 2013-09-10 Probiodrug Ag Inhibitors
EP3049057A1 (en) * 2013-09-25 2016-08-03 Sun Pharmaceutical Industries Ltd Oral liquid pharmaceutical composition of a dpp-iv inhibitor
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MX2017011586A (es) 2015-03-09 2017-10-26 Intekrin Therapeutics Inc Metodos para el tratamiento de enfermedad de higado graso no alcoholico y/o lipodistrofia.
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Citations (282)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2961377A (en) 1957-08-05 1960-11-22 Us Vitamin Pharm Corp Oral anti-diabetic compositions and methods
US3322756A (en) 1963-05-18 1967-05-30 Hoechst Ag 2-aminoalkyl-3-hydrocarbon quinazolones-(4)
US3544570A (en) 1967-08-18 1970-12-01 Bayer Ag 1,2,4-triazine-5-ones
DE2150686A1 (de) 1971-10-12 1973-04-19 Basf Ag 6-amino-uracil-5-carbonsaeurethioamide
FR2162106A1 (en) 1971-12-02 1973-07-13 Byk Gulden Lomberg Chem Fab 4-pyrimidone derivs - as hypotensives and analgesics
US3823135A (en) 1972-12-26 1974-07-09 Shell Oil Co Pyrimidone herbicides
GB1377642A (en) 1971-01-14 1974-12-18 Koninklijke Gist Spiritus Penicillanic and cephalosporanic acid derivatives
DE2361551A1 (de) 1973-12-11 1975-06-19 Basf Ag Wasserloesliche azofarbstoffe
US3960949A (en) 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
GB1441665A (en) 1972-09-11 1976-07-07 Commw Scient Ind Res Org Pyridinium salts
DE2500024A1 (de) 1975-01-02 1976-07-08 Basf Ag Wasserloesliche azofarbstoffe
GB1464248A (en) 1973-11-01 1977-02-09 Ici Ltd Substituted triazinediones their preparation and use as herbicides
JPS535180A (en) 1976-07-01 1978-01-18 Sumitomo Chem Co Ltd Preparation of 3,4-dihydro-2 (1h) quinazoline derivatives
DE2801289A1 (de) 1977-05-05 1979-05-03 Hoechst Ag Pyrimido(6,1-a)isochinolin-2-on- derivate
US4494978A (en) 1976-12-30 1985-01-22 Chevron Research Company Herbicidal N-(N'-hydrocarbyloxycarbamylalkyl)-2,6-dialkyl-alpha-haloacetanilides
GB2143542A (en) 1983-06-28 1985-02-13 Ciba Geigy Ag Chromogenic quinazolones
US4687777A (en) 1985-01-19 1987-08-18 Takeda Chemical Industries, Ltd. Thiazolidinedione derivatives, useful as antidiabetic agents
US4935493A (en) 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
EP0378255A2 (en) 1989-01-09 1990-07-18 Janssen Pharmaceutica N.V. 2-Aminopyrimidinone derivatives
GB2230527A (en) 1989-04-21 1990-10-24 Ici Plc 4-(substituted amino)-pyrimidinium derivatives as cardiovascular agents
US5002953A (en) 1987-09-04 1991-03-26 Beecham Group P.L.C. Novel compounds
EP0547442A1 (en) 1991-12-16 1993-06-23 E.R. SQUIBB & SONS, INC. Dihydropyrimidin derivatives used as A-II receptor antagonists
EP0547514A3 (de) 1991-12-18 1993-07-14 MERCK PATENT GmbH Imidazopyridinderivate mit angiotensin-II antagonistischen Eigenschaften
EP0587377A2 (en) 1992-09-10 1994-03-16 Eli Lilly And Company Thiazolidinone derivatives as hypoglycemic agents and for treating Alzheimer's disease
EP0574846A3 (en) 1992-06-17 1994-07-06 Merck Patent Gmbh Imidazopyridines as angiotensin ii antagonistes
US5366862A (en) 1990-02-14 1994-11-22 Receptor Laboratories, Inc. Method for generating and screening useful peptides
US5387512A (en) 1991-06-07 1995-02-07 Merck & Co. Inc. Preparation of 3-[z-benzoxazol-2-yl)ethyl]-5-(1-hydroxyethyl)-6-methyl-2-(1H)-pyridinone by biotransformation
EP0657452A1 (de) 1993-12-06 1995-06-14 MERCK PATENT GmbH Imidazopyridine
US5433955A (en) 1989-01-23 1995-07-18 Akzo N.V. Site specific in vivo activation of therapeutic drugs
US5462928A (en) 1990-04-14 1995-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type IV
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5543396A (en) 1994-04-28 1996-08-06 Georgia Tech Research Corp. Proline phosphonate derivatives
US5580979A (en) 1994-03-15 1996-12-03 Trustees Of Tufts University Phosphotyrosine peptidomimetics for inhibiting SH2 domain interactions
US5601986A (en) 1994-07-14 1997-02-11 Amgen Inc. Assays and devices for the detection of extrahepatic biliary atresia
US5614379A (en) 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
US5614492A (en) 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US5624894A (en) 1992-09-17 1997-04-29 University Of Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
EP0442473B1 (en) 1990-02-15 1998-08-19 Takeda Chemical Industries, Ltd. Pyrimidinedione derivatives, their production and use
US5798344A (en) 1994-03-08 1998-08-25 Otsuka Pharmaceutical Factory, Inc. Phosphonic ester derivatives of quinazolinones
US5811281A (en) 1993-07-12 1998-09-22 Cornell Research Foundation, Inc. Immortalized intestinal epithelial cell lines
US5811278A (en) 1995-07-21 1998-09-22 Ajinomoto Co., Inc. Dipeptidyl peptidase IV from Xanthomonas maltophilia and process for producing the same
US5814460A (en) 1990-02-14 1998-09-29 Diatide, Inc. Method for generating and screening useful peptides
US5885997A (en) 1996-07-01 1999-03-23 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5939560A (en) 1993-12-03 1999-08-17 Ferring B.V. Inhibitors of DP-mediated processes, compositions and therapeutic methods thereof
US5965532A (en) 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US5985884A (en) 1996-07-01 1999-11-16 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
US6011155A (en) 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
EP0505893B1 (de) 1991-03-27 2000-06-21 MERCK PATENT GmbH Imidazopyridine
US6090786A (en) 1994-06-10 2000-07-18 Fondatech Benelux N.V. Serine proteases, their activity and their synthetic inhibitors
US6107317A (en) 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6110949A (en) 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6129911A (en) 1998-07-10 2000-10-10 Rhode Island Hospital, A Lifespan Partner Liver stem cell
US6156739A (en) 1997-02-01 2000-12-05 Newcastle University Ventures Limited Quinazolinone compounds
WO2000076986A1 (de) 1999-06-10 2000-12-21 Probiodrug Gesellschaft für Arzneimittelforschung mbH Verfahren zur herstellung von thiazolidin
US6166063A (en) 1998-12-10 2000-12-26 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6184020B1 (en) 1997-12-16 2001-02-06 Novo Nordisk Biotech, Inc. Polypeptides having aminopeptidase activity and nucleic acids encoding same
WO2001014318A2 (de) 1999-08-24 2001-03-01 Probiodrug Ag Neue effektoren der dipeptidyl peptidase iv zur topischen anwendung
WO2001023364A1 (en) 1999-09-28 2001-04-05 Merck Patent Gmbh Quinazolinones
US6214340B1 (en) 1997-11-18 2001-04-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Physiologically active substance sulphostin, process for producing the same, and use thereof
EP0748800B1 (en) 1995-06-09 2001-05-09 F. Hoffmann-La Roche Ag Pyrimidinedione, pyrimidinetrione, triazinedione derivatives as alpha-1-adrenergic receptor antagonists
WO2001034594A1 (en) 1999-11-12 2001-05-17 Guilford Pharmaceuticals, Inc. Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
US6235493B1 (en) 1997-08-06 2001-05-22 The Regents Of The University Of California Amino acid substituted-cresyl violet, synthetic fluorogenic substrates for the analysis of agents in individual in vivo cells or tissue
EP0702013B1 (de) 1994-09-15 2001-06-13 MERCK PATENT GmbH Imidazopyridine
US6251391B1 (en) 1999-10-01 2001-06-26 Klaire Laboratories, Inc. Compositions containing dipepitidyl peptidase IV and tyrosinase or phenylalaninase for reducing opioid-related symptons
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6261794B1 (en) 1999-10-14 2001-07-17 Saint Louis University Methods for identifying inhibitors of methionine aminopeptidases
US6265551B1 (en) 1995-06-01 2001-07-24 Dana-Farber Cancer Institute, Inc. Form of dipeptidylpeptidase IV (CD26) found in human serum, antibodies thereto, and uses thereof
WO2001052825A2 (en) 2000-01-21 2001-07-26 Novartis Ag Combinations comprising dipeptidylpeptidase-iv inhibitors and antidiabetic agents
WO2001056988A1 (fr) 2000-02-01 2001-08-09 Kirin Beer Kabushiki Kaisha Composes contenant de l'azote et possedant une activite d'inhibition des kinases, et medicaments comprenant ces composes
US20010020006A1 (en) 1998-06-24 2001-09-06 Hans-Ulrich Demuth Compounds of unstable DP IV-inhibitors
EP1136482A1 (en) 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-Amino-3-(alkyl)-pyrimidone derivatives as GSK3beta inhibitors
US6303661B1 (en) 1996-04-25 2001-10-16 Probiodrug Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals
US20010031780A1 (en) 2000-01-24 2001-10-18 Anders Kanstrup New therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US6309868B1 (en) 1997-07-05 2001-10-30 Nestec S.A. Cloning of the prolyl-dipeptidyl-peptidase from Aspergillus oryzae
US6319893B1 (en) 1998-07-31 2001-11-20 Probiodrug Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV
US6325989B1 (en) 1995-06-01 2001-12-04 Dana-Farber Cancer Institute, Inc. Form of dipeptidylpeptidase IV (CD26) found in human serum
US20010051646A1 (en) 2000-03-31 2001-12-13 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
WO2001096295A2 (en) 2000-06-13 2001-12-20 Novartis Ag 2-cyanopyrrolidine derivatives and their use as medicaments
WO2001097808A1 (en) 2000-06-19 2001-12-27 Smithkline Beecham Plc Combinations of depeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabete mellitus
US6335429B1 (en) 1997-10-10 2002-01-01 Cytovia, Inc. Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof
US6337069B1 (en) 2001-02-28 2002-01-08 B.M.R.A. Corporation B.V. Method of treating rhinitis or sinusitis by intranasally administering a peptidase
WO2002002560A2 (en) 2000-07-04 2002-01-10 Novo Nordisk A/S Purine-2,6-diones which are inhibitors of the enzyme dipeptidyl peptidase iv (dpp-iv)
US20020006899A1 (en) 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
US20020016100A1 (en) 2000-07-25 2002-02-07 Yazaki Coroporation Connector supporting structure
US20020019411A1 (en) 2000-03-10 2002-02-14 Robl Jeffrey A. Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
WO2002020488A2 (en) 2000-09-06 2002-03-14 F. Hoffmann-La Roche Ag Quinoline and quinazoline derivatives as ligands for the neuropeptide y receptor
US20020037829A1 (en) 2000-08-23 2002-03-28 Aronson Peter S. Use of DPPIV inhibitors as diuretic and anti-hypertensive agents
US20020041871A1 (en) 2000-06-01 2002-04-11 Brudnak Mark A. Genomeceutical and/or enzymatic composition and method for treating autism
EP1197799A1 (en) 2000-09-27 2002-04-17 Fuji Photo Film Co., Ltd. Dye-forming coupler, silver halide photographic light-sensitive material, and method for producing an azomethine dye
US20020049153A1 (en) 1999-05-17 2002-04-25 BRIDON Dominique P. Long lasting insulinoptropic peptides
US20020049164A1 (en) 1998-06-24 2002-04-25 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
WO2002034242A2 (en) 2000-10-27 2002-05-02 Probiodrug Ag Method for the treatment of neurological and neuropsychological disorders
US20020061839A1 (en) 1998-03-09 2002-05-23 Scharpe Simon Lodewijk Serine peptidase modulators
US20020077340A1 (en) 2000-11-20 2002-06-20 Richard Sulsky Pyridone inhibitors of fatty acid binding protein and method
US20020082292A1 (en) 2000-09-27 2002-06-27 Sahoo Soumya P. Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
US20020103242A1 (en) 2000-10-31 2002-08-01 Sahoo Soumya P. Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
EP1229024A1 (en) 1999-10-08 2002-08-07 Meiji Seika Kaisha Ltd. m-SUBSTITUTED BENZOIC ACID DERIVATIVES EXHIBITING INTEGRIN ALPHA-V BETA-3 ANTAGONISM
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US20020115843A1 (en) 2000-10-12 2002-08-22 Steve Oi Novel serine protease genes related to DPPIV
US6448045B1 (en) 2000-03-10 2002-09-10 The Regents Of The University Of California Inducing insulin gene expression in pancreas cells expressing recombinant PDX-1
US6447772B1 (en) 1999-10-01 2002-09-10 Klaire Laboratories, Inc. Compositions and methods relating to reduction of symptoms of autism
US20020132979A1 (en) 2000-04-01 2002-09-19 Wen-Tien Chen Compositions and methods for inhibition of cancer invasion and angiogenesis
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
US20020147130A1 (en) 1997-05-07 2002-10-10 Huber Brigitte T. Treatment of hiv
US20020147157A1 (en) 2000-10-30 2002-10-10 Connor Gregory S. Combination therapy comprising anti-diabetic and anticonvulsant agents
US20020155565A1 (en) 2000-11-10 2002-10-24 Pilar Garin-Chesa FAP-activated anti-tumor compounds
WO2002083109A1 (en) 2001-04-11 2002-10-24 Ferring Bv Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase iv
US20020164759A1 (en) 2000-11-08 2002-11-07 The University Of Georgia Research Foundation, Inc Dipeptidylpeptidases and methods of use
US20020169159A1 (en) 2000-12-11 2002-11-14 Tularik Inc. CXCR3 antagonists
US6485955B1 (en) 1997-10-06 2002-11-26 The Trustees Of Tufts University Quiescent cell dipeptidyl peptidase: a novel cytoplasmic serine protease
JP2002338466A (ja) 2001-03-15 2002-11-27 Tanabe Seiyaku Co Ltd 医薬組成物
US20020183367A1 (en) 2001-04-12 2002-12-05 Sulsky Richard B. 2,1-Oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
US6495544B2 (en) 2000-08-01 2002-12-17 Pharmacia Corporation Homoiminopiperidinyl hexanoic acid inhibitors of inducible nitric oxide synthase
US20020198205A1 (en) 2001-02-24 2002-12-26 Frank Himmelsbach Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20020198380A1 (en) 2001-03-30 2002-12-26 Werner Belzer Process for preparing 4,6-diaminopyrimido[5,4-d]pyrimidines
WO2003000181A2 (en) 2001-06-20 2003-01-03 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
WO2003002595A2 (en) 2001-06-27 2003-01-09 Probiodrug Ag Dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents
WO2003002593A2 (en) 2001-06-27 2003-01-09 Probiodrug Ag Peptide structures useful for competitive modulation of dipeptidyl peptidase iv catalysis
WO2003007888A2 (en) 2001-07-20 2003-01-30 Adipogenix, Inc. Fat accumulation-modulating compounds
US6518277B1 (en) 2000-04-25 2003-02-11 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US6521644B1 (en) 1999-03-23 2003-02-18 Ferring Bv Compositions for promoting growth
WO2003016335A2 (en) 2001-08-13 2003-02-27 Probiodrug Ag Irreversible cysteine protease inhibitors of legumain
US20030040478A1 (en) 1999-12-08 2003-02-27 Drucker Daniel J Chemotherapy treatment
US6528486B1 (en) 1999-07-12 2003-03-04 Zealand Pharma A/S Peptide agonists of GLP-1 activity
US20030045464A1 (en) 1997-12-16 2003-03-06 Hermeling Ronald Norbert Glucagon-like peptide-1 crystals
WO2003022871A2 (en) 2001-09-06 2003-03-20 Probiodrug Ag Peptides having a c- terminal hydroxylamino group as inhibitors of dipeptidyl peptidase i
US20030055052A1 (en) 2000-11-10 2003-03-20 Stefan Peters FAP-activated anti-tumor compounds
US20030060412A1 (en) 2000-01-27 2003-03-27 Prouty Walter Francis Process for solubilizing glucagon-like peptide 1compounds
US20030060434A1 (en) 1997-02-18 2003-03-27 Loretta Nielsen Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms
US20030060494A1 (en) 2001-05-18 2003-03-27 Nobuyuki Yasuda Pharmaceutical use of N-carbamoylazole derivatives
WO2003026652A1 (en) 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003027080A1 (en) 2001-09-21 2003-04-03 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
US6545170B2 (en) 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US20030069234A1 (en) 2001-06-06 2003-04-10 Medina Julio C. CXCR3 antagonists
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
WO2003030946A1 (en) 2001-10-09 2003-04-17 Novartis Ag Regulation of insulin production
WO2003033524A2 (en) 2001-10-12 2003-04-24 Probiodrug Ag Peptidyl ketones as inhibitors of dpiv
US6555519B2 (en) 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
WO2003035640A1 (fr) 2001-10-22 2003-05-01 Eisai Co., Ltd. Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes
US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
JP2003128551A (ja) 2001-08-15 2003-05-08 Sankyo Co Ltd 新規抗糖尿病医薬組成物
US20030087950A1 (en) 2001-03-28 2003-05-08 Denanteuil Guillaume New alpha-amino acid sulphonyl compounds
WO2003037888A1 (en) 2001-09-21 2003-05-08 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
US20030087935A1 (en) 1999-09-22 2003-05-08 Cheng Peter T. Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030092697A1 (en) 2001-05-30 2003-05-15 Cheng Peter T. Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method
WO2003040174A2 (en) 2001-11-09 2003-05-15 Probiodrug Ag Substituted amino ketone compounds
US20030089935A1 (en) 2001-11-13 2003-05-15 Macronix International Co., Ltd. Non-volatile semiconductor memory device with multi-layer gate insulating structure
US20030096857A1 (en) 1999-11-30 2003-05-22 Evans David Michael Novel antidiabetic agents
US20030100563A1 (en) 2001-07-06 2003-05-29 Edmondson Scott D. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2003045977A2 (en) 2001-11-26 2003-06-05 Trustees Of Tufts College Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes
US20030105077A1 (en) 2001-07-03 2003-06-05 Kanstrup Anders Bendtz Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030103968A1 (en) 2001-04-12 2003-06-05 Andree Amelsberg Use of alpha specific antibody BIBH1 in the treatment of cancer
WO2003045228A2 (en) 2001-11-26 2003-06-05 Trustees Of Tufts College Methods for treating autoimmune disorders, and reagents related thereto
WO2003048081A2 (en) 2001-12-04 2003-06-12 Bristol-Myers Squibb Company Glycinamides as factor xa inhibitors
US20030119750A1 (en) 2001-06-27 2003-06-26 Hans-Ulrich Demuth Use of dipeptidyl peptidase IV inhibitors
US20030119738A1 (en) 2001-09-06 2003-06-26 Andre Niestroj Novel inhibitors of dipeptidyl peptidase I
US20030119736A1 (en) 2001-04-02 2003-06-26 Hans-Ulrich Demuth Methods for improving islet signaling in diabetes mellitus and for its prevention
US6586198B2 (en) 2000-10-31 2003-07-01 Vanderbilt University Method of identifying susceptibility to angiotensin converting enzyme inhibto- and vasopeptidase-inhibitor-associated angioedema
US20030125304A1 (en) 2001-11-09 2003-07-03 Hans-Ulrich Demuth Substituted amino ketone compounds
US20030130306A1 (en) 2001-11-06 2003-07-10 Pratik Devasthale Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030130281A1 (en) 2001-10-26 2003-07-10 Markus Boehringer DPP IV inhibitors
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
WO2003057200A2 (en) 2002-01-11 2003-07-17 Novo Nordisk A/S Compositions comprising inhibitors of dpp-iv and nep enzymes for the treatment of diabetes
US20030135023A1 (en) 2001-06-27 2003-07-17 Hans-Ulrich Demuth Peptide structures useful for competitive modulation of dipeptidyl peptidase IV catalysis
US20030139429A1 (en) 2001-09-27 2003-07-24 Cohen David Saul Combinations
US20030144206A1 (en) 2001-12-29 2003-07-31 Knudsen Lotte Bjerre Combined use of a GLP-1 compound and modulator of diabetic late complications
US20030149071A1 (en) 2001-12-27 2003-08-07 Gobbi Luca Claudio Pyrido [2,1-a] isoquinoline derivatives
WO2003063903A2 (en) 2002-02-01 2003-08-07 Probiodrug Ag Modulation of t lymphocytes using dp iv inhibitors
US20030153509A1 (en) 1998-02-02 2003-08-14 Bachovchin William W. Method of regulating glucose metabolism, and reagents related thereto
US6608038B2 (en) 2000-03-15 2003-08-19 Novartis Ag Methods and compositions for treatment of diabetes and related conditions via gene therapy
US20030162820A1 (en) 2002-02-28 2003-08-28 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US20030166662A1 (en) 2000-08-11 2003-09-04 Pfizer Inc. Treatment of the insulin resistance syndrome
US20030166690A1 (en) 2001-12-14 2003-09-04 Soren Ebdrup Use of compounds for decreasing activity of hormone-sensitive
US20030166578A1 (en) 2000-06-19 2003-09-04 Arch Jonathan Robert Sanders Combinations od dipeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabetes mellitus
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US20030171411A1 (en) 2001-12-21 2003-09-11 Kodra Janos Tibor Amide derivatives as therapeutic agents
US20030171358A1 (en) 1999-04-20 2003-09-11 Lone Jeppesen New compounds, their preparation and use
US6620821B2 (en) 2000-06-15 2003-09-16 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US6620910B1 (en) 1998-04-10 2003-09-16 Les Laboratoires Servier Peptide compounds analogues of the glucagon-like peptide-1 (7-37)
US20030176357A1 (en) 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
WO2003076418A1 (en) 2002-03-07 2003-09-18 X-Ceptor Therapeutics, Inc. Quinazolinone modulators of nuclear receptors
US20030181497A1 (en) 2001-12-21 2003-09-25 Ping Chen Heterocyclic acridone inhibitors of IMPDH enzyme
US6627636B2 (en) 2000-06-15 2003-09-30 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US20030186963A1 (en) 2001-09-14 2003-10-02 Dorwald Florencio Zaragoza Substituted piperidines
US20030187254A1 (en) 2002-02-27 2003-10-02 Pfizer Inc. Acetyl-CoA carboxylase inhibitors
US20030191112A1 (en) 2001-10-12 2003-10-09 Dorwald Florencio Zaragoza Novel substituted piperidines
WO2003082898A2 (en) 2002-03-28 2003-10-09 Prosidion Ltd. Novel analogues of glucose-dependent insulinotropic polypeptide
US20030195190A1 (en) 2002-02-01 2003-10-16 Bernd Peschke Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes
US20030195188A1 (en) 2002-02-13 2003-10-16 Markus Boehringer Pyridine and quinoline derivatives
US20030199528A1 (en) 2001-09-19 2003-10-23 Kanstrup Anders B. Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030199672A1 (en) 1996-08-30 2003-10-23 Knudsen Liselotte Bjerre Derivatives of GLP-1 analogs
US20030199451A1 (en) 2000-01-28 2003-10-23 Mogensen John Patrick Combination therapy using a dual PPAR-a/PPAR-y activator and a GLP-1 derivative for the treatment of metabolic syndrome and related diseases and disorders
US20030203946A1 (en) 2000-11-17 2003-10-30 Carsten Behrens Glucagon antagonists/inverse agonists
WO2003092605A2 (en) 2002-04-30 2003-11-13 Trustees Of Tufts College Protease inhibitors
US20030216450A1 (en) 2000-04-26 2003-11-20 Evans David Michael Inhibitors of dipeptidyl peptidase IV
US20030216382A1 (en) 2002-02-13 2003-11-20 Markus Boehringer Pyridine and pyrimidine derivatives
US20030220345A1 (en) 2000-08-04 2003-11-27 Hamby James Marino 2-(4-Pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimdin-7-ones
WO2003099818A1 (en) 2002-05-23 2003-12-04 Chiron Corporation Substituted quinazolinone compounds
WO2003099279A1 (en) 2002-05-29 2003-12-04 Novartis Ag Combination of a dpp iv inhibitor and a cardiovascular compound
US20030225102A1 (en) 2002-04-08 2003-12-04 Torrent Pharmaceuticals Ltd. Novel compounds and therapeutic uses thereof
US6664273B2 (en) 2001-11-26 2003-12-16 Schering Corporation Piperidine based MCH antagonists for treatment of obesity and CNS disorders
WO2003106416A2 (en) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Chemical process
US20040002609A1 (en) 2002-06-04 2004-01-01 Pfizer Inc. Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
US20040002495A1 (en) 2002-05-20 2004-01-01 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
US20040006062A1 (en) 2002-05-06 2004-01-08 Smallheer Joanne M. Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US20040009998A1 (en) 2001-10-01 2004-01-15 Dhar T. G. Murali Spiro-hydantoin compounds useful as anti-inflammatory agents
US20040009972A1 (en) 2002-06-17 2004-01-15 Ding Charles Z. Benzodiazepine inhibitors of mitochondial F1F0 ATP hydrolase and methods of inhibiting F1F0 ATP hydrolase
WO2004017989A1 (en) 2002-08-09 2004-03-04 Prosidion Ltd. Methods for improving islet signaling in diabetes mellitus and for its prevention
US6706742B2 (en) 2001-05-15 2004-03-16 Les Laboratories Servier Alpha-amino-acid compounds
EP1398032A1 (en) 2002-09-10 2004-03-17 PheneX Pharmaceuticals AG 4-Oxo-quinazolines as LXR nuclear receptor binding compounds
US20040053369A1 (en) 2000-10-27 2004-03-18 Abbott Catherine Anne Dipeptidyl peptidases
US20040054171A1 (en) 2002-07-04 2004-03-18 Jensen Anette Frost Polymorphic forms of a 4H-thieno[3,2-E]-1,2,4-thiadiazine 1,1-dioxide derivative
US6710040B1 (en) 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
US20040058876A1 (en) 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
US20040063935A1 (en) 2000-10-06 2004-04-01 Kosuke Yasuda Aliphatic nitrogenous five-membered ring compounds
WO2004031374A2 (en) 2002-09-18 2004-04-15 Prosidion Ltd. Secondary binding site of dipeptidyl peptidase iv (dp iv)
US20040072892A1 (en) 2000-11-10 2004-04-15 Hiroshi Fukushima Cyanopyrrolidine derivatives
US20040072874A1 (en) 2002-09-30 2004-04-15 Nagaaki Sato N-substituted-2-oxodihydropyridine derivatives
JP2004123738A (ja) 2002-09-11 2004-04-22 Takeda Chem Ind Ltd 徐放性製剤
US20040082497A1 (en) 2000-04-26 2004-04-29 Evans David Michael Inhibitors of dipeptidyl peptidase IV
US20040082607A1 (en) 2001-02-02 2004-04-29 Satoru Oi Fused heterocyclic compounds
WO2004037176A2 (en) 2002-10-21 2004-05-06 Bristol-Myers Squibb Company Quinazolinones and derivatives thereof as factor xa inhibitors
US20040092478A1 (en) 2001-03-19 2004-05-13 Rothermel John D. Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative
US20040097510A1 (en) 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20040106656A1 (en) 2001-03-27 2004-06-03 Ashton Wallace T Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20040106802A1 (en) 2002-04-08 2004-06-03 Torrent Pharmaceuticals Ltd. Novel compounds and therapeutic uses thereof
US20040106655A1 (en) 2000-08-10 2004-06-03 Hiroshi Kitajima Proline derivatives and the use thereof as drugs
US6747035B2 (en) 2001-08-13 2004-06-08 Warner-Lambert Llc 1-alkyl or 1-cycloalkyltriazolo[4,3-a]quinazolin-5-ones as phosphodiesterase inhibitors
US20040110817A1 (en) 2002-11-18 2004-06-10 Pfizer Inc Dipeptidyl peptidase IV inhibiting fluorinated cyclic amides
US20040116328A1 (en) 2002-06-06 2004-06-17 Eisai Co., Ltd. Condensed imidazole derivatives
DE10256264A1 (de) 2002-12-03 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Imidazo-pyridinone und Imidazo-pyridazinone, ihre Herstellung und ihre Verwendung als Arzneimittel
US20040138215A1 (en) 2002-11-21 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20040138148A1 (en) 2001-02-14 2004-07-15 Nobuhiko Fushimi Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof
US20040138214A1 (en) 2002-11-08 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20040147434A1 (en) 2001-01-02 2004-07-29 Siegfried Ansorge Use of enzyme inhibitors of the dipeptidypeptidase iv (ec3.3.14.5) in addition to the aminopeptidase n (ec 3.4.11.2), individually or in a combination thereof, and pharmaceutical preparations thereof for the prevention and/or therapy of ischaemia-caused acute and chronic neurodegenerative process and illnesses, for example
WO2004062613A2 (en) 2003-01-13 2004-07-29 Bristol-Myers Squibb Company Hiv integrase inhibitors
US20040152745A1 (en) 1999-11-12 2004-08-05 Guilford Pharmaceuticals, Inc. Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors
US20040166125A1 (en) 2002-08-22 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US20040167341A1 (en) 2001-06-27 2004-08-26 Haffner Curt Dale Pyrrolidines as dipeptidyl peptidase inhibitors
US20040171848A1 (en) 2001-06-27 2004-09-02 Haffner Curt Dale Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US20040171104A1 (en) 1997-05-16 2004-09-02 Novozymes Biotech, Inc. Polypeptides having dipeptidyl aminopeptidase activity and nucleic acids encoding same
US20040176428A1 (en) 2001-06-20 2004-09-09 Edmondson Scott D. Dipeptidyl peptidase inhibitors for the treatment of diabetes
US20040180925A1 (en) 2000-12-27 2004-09-16 Kenji Matsuno Dipeptidylpeptidase-IV inhibitor
WO2004085408A1 (en) 2003-03-26 2004-10-07 Mitsubishi Pharma Corporation 2, 3, 6-trisubstituted-4-pyrimidone derivatives
US20040198786A1 (en) 2003-02-27 2004-10-07 Aventis Pharma Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
US20040229820A1 (en) 1991-10-22 2004-11-18 Bachovchin William W. Inhibitors of dipeptidyl-aminopeptidase type IV
US20040229848A1 (en) 2003-05-05 2004-11-18 Hans-Ulrich Demuth Glutaminyl based DP IV-inhibitors
US20040242566A1 (en) 2003-03-25 2004-12-02 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20040242636A1 (en) 2001-06-27 2004-12-02 Haffner Curt Dale Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US20040254226A1 (en) 2003-05-14 2004-12-16 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20040254167A1 (en) 2002-10-18 2004-12-16 Tesfaye Biftu Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20040259902A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
US20040259919A1 (en) 2002-10-23 2004-12-23 Magnin David R. Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods
US20040259843A1 (en) 2002-09-19 2004-12-23 Madar David J. Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20040259883A1 (en) 2001-09-14 2004-12-23 Hiroshi Sakashita Thiazolidine derivative and medicinal use thereof
US20040259903A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
US20050014732A1 (en) 2003-03-14 2005-01-20 Pharmacia Corporation Combination of an aldosterone receptor antagonist and an anti-diabetic agent
US20050020574A1 (en) 2002-12-03 2005-01-27 Boehringer Ingelheim Pharma Gmbh Co. Kg New substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions
US20050026921A1 (en) 2003-06-18 2005-02-03 Boehringer Ingelheim International Gmbh New imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US20050032804A1 (en) 2003-06-24 2005-02-10 Cypes Stephen Howard Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
US20050038020A1 (en) 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050043299A1 (en) 2001-10-23 2005-02-24 Ferring B. V. Inhibitors of dipeptidyl peptidase iv
US20050043292A1 (en) 2003-08-20 2005-02-24 Pfizer Inc Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors
US20050058635A1 (en) 2003-05-05 2005-03-17 Hans-Ulrich Demuth Use of effectors of glutaminyl and glutamate cyclases
US20050065144A1 (en) 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050065145A1 (en) 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050065148A1 (en) 2003-08-13 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050261271A1 (en) 2004-03-15 2005-11-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US6998502B1 (en) 2002-09-05 2006-02-14 Sabinsa Corporation Convenient process of manufacture for difluoromethylornithine and related compounds
US7125881B2 (en) 2002-06-24 2006-10-24 Astrazeneca Ab Use of pyrimidine—or triazine—2 carbonitiles for treating diseases associated with cysteine prostease activity and novel pyrimidine-2-carbonitile derivatives
US20070060530A1 (en) 2005-09-14 2007-03-15 Christopher Ronald J Administration of dipeptidyl peptidase inhibitors
US20070060528A1 (en) 2005-09-14 2007-03-15 Christopher Ronald J Administration of dipeptidyl peptidase inhibitors
US20070066635A1 (en) 2005-09-16 2007-03-22 Mark Andres Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US7304086B2 (en) 2004-02-05 2007-12-04 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7576076B2 (en) 2004-07-02 2009-08-18 Corcept Therapeutics, Inc. Modified pyrimidine glucocorticoid receptor modulators

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3710795A (en) 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US4044126A (en) 1972-04-20 1977-08-23 Allen & Hanburys Limited Steroidal aerosol compositions and process for the preparation thereof
GB1429184A (en) 1972-04-20 1976-03-24 Allen & Hanburys Ltd Physically anti-inflammatory steroids for use in aerosols
USRE28819E (en) 1972-12-08 1976-05-18 Syntex (U.S.A.) Inc. Dialkylated glycol compositions and medicament preparations containing same
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4358603A (en) 1981-04-16 1982-11-09 Syntex (U.S.A.) Inc. Acetal stabilized prostaglandin compositions
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
WO1994003055A1 (en) 1992-07-31 1994-02-17 The Government Of The United States Of America, Asrepresented By The Secretary Of The Department Of Health And Human Services Producing increased numbers of hematopoietic cells by administering inhibitors of dipeptidyl peptidase iv
US6017317A (en) * 1997-03-26 2000-01-25 Becton Dickinson And Company Assembly for collecting blood or other body fluids
US6432939B1 (en) * 1999-12-02 2002-08-13 Michael Oettel 17a-hydroxy-4-androstene-3-one and derivatives thereof
US6518269B1 (en) * 2000-07-28 2003-02-11 University Of Arizona Foundation Cancer treatment
TW200407143A (en) * 2002-05-21 2004-05-16 Bristol Myers Squibb Co Pyrrolotriazinone compounds and their use to treat diseases

Patent Citations (355)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2961377A (en) 1957-08-05 1960-11-22 Us Vitamin Pharm Corp Oral anti-diabetic compositions and methods
US3322756A (en) 1963-05-18 1967-05-30 Hoechst Ag 2-aminoalkyl-3-hydrocarbon quinazolones-(4)
US3544570A (en) 1967-08-18 1970-12-01 Bayer Ag 1,2,4-triazine-5-ones
GB1377642A (en) 1971-01-14 1974-12-18 Koninklijke Gist Spiritus Penicillanic and cephalosporanic acid derivatives
US3960949A (en) 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
DE2150686A1 (de) 1971-10-12 1973-04-19 Basf Ag 6-amino-uracil-5-carbonsaeurethioamide
FR2162106A1 (en) 1971-12-02 1973-07-13 Byk Gulden Lomberg Chem Fab 4-pyrimidone derivs - as hypotensives and analgesics
GB1441665A (en) 1972-09-11 1976-07-07 Commw Scient Ind Res Org Pyridinium salts
US3823135A (en) 1972-12-26 1974-07-09 Shell Oil Co Pyrimidone herbicides
GB1464248A (en) 1973-11-01 1977-02-09 Ici Ltd Substituted triazinediones their preparation and use as herbicides
DE2361551A1 (de) 1973-12-11 1975-06-19 Basf Ag Wasserloesliche azofarbstoffe
DE2500024A1 (de) 1975-01-02 1976-07-08 Basf Ag Wasserloesliche azofarbstoffe
JPS535180A (en) 1976-07-01 1978-01-18 Sumitomo Chem Co Ltd Preparation of 3,4-dihydro-2 (1h) quinazoline derivatives
US4494978A (en) 1976-12-30 1985-01-22 Chevron Research Company Herbicidal N-(N'-hydrocarbyloxycarbamylalkyl)-2,6-dialkyl-alpha-haloacetanilides
DE2801289A1 (de) 1977-05-05 1979-05-03 Hoechst Ag Pyrimido(6,1-a)isochinolin-2-on- derivate
GB2143542A (en) 1983-06-28 1985-02-13 Ciba Geigy Ag Chromogenic quinazolones
US4687777A (en) 1985-01-19 1987-08-18 Takeda Chemical Industries, Ltd. Thiazolidinedione derivatives, useful as antidiabetic agents
US5614492A (en) 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US5002953A (en) 1987-09-04 1991-03-26 Beecham Group P.L.C. Novel compounds
US4935493A (en) 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
EP0378255A2 (en) 1989-01-09 1990-07-18 Janssen Pharmaceutica N.V. 2-Aminopyrimidinone derivatives
US5433955A (en) 1989-01-23 1995-07-18 Akzo N.V. Site specific in vivo activation of therapeutic drugs
GB2230527A (en) 1989-04-21 1990-10-24 Ici Plc 4-(substituted amino)-pyrimidinium derivatives as cardiovascular agents
US5814460A (en) 1990-02-14 1998-09-29 Diatide, Inc. Method for generating and screening useful peptides
US5366862A (en) 1990-02-14 1994-11-22 Receptor Laboratories, Inc. Method for generating and screening useful peptides
EP0442473B1 (en) 1990-02-15 1998-08-19 Takeda Chemical Industries, Ltd. Pyrimidinedione derivatives, their production and use
US5462928A (en) 1990-04-14 1995-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type IV
EP0505893B1 (de) 1991-03-27 2000-06-21 MERCK PATENT GmbH Imidazopyridine
US5387512A (en) 1991-06-07 1995-02-07 Merck & Co. Inc. Preparation of 3-[z-benzoxazol-2-yl)ethyl]-5-(1-hydroxyethyl)-6-methyl-2-(1H)-pyridinone by biotransformation
US20040229820A1 (en) 1991-10-22 2004-11-18 Bachovchin William W. Inhibitors of dipeptidyl-aminopeptidase type IV
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
EP0547442A1 (en) 1991-12-16 1993-06-23 E.R. SQUIBB & SONS, INC. Dihydropyrimidin derivatives used as A-II receptor antagonists
EP0547514A3 (de) 1991-12-18 1993-07-14 MERCK PATENT GmbH Imidazopyridinderivate mit angiotensin-II antagonistischen Eigenschaften
EP0574846A3 (en) 1992-06-17 1994-07-06 Merck Patent Gmbh Imidazopyridines as angiotensin ii antagonistes
EP0587377A2 (en) 1992-09-10 1994-03-16 Eli Lilly And Company Thiazolidinone derivatives as hypoglycemic agents and for treating Alzheimer's disease
US5624894A (en) 1992-09-17 1997-04-29 University Of Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
US5811281A (en) 1993-07-12 1998-09-22 Cornell Research Foundation, Inc. Immortalized intestinal epithelial cell lines
US6201132B1 (en) 1993-12-03 2001-03-13 Ferring B.V. Inhibitors of DP-mediated processes, compositions, and therapeutic methods thereof
US5939560A (en) 1993-12-03 1999-08-17 Ferring B.V. Inhibitors of DP-mediated processes, compositions and therapeutic methods thereof
EP0657452A1 (de) 1993-12-06 1995-06-14 MERCK PATENT GmbH Imidazopyridine
US5798344A (en) 1994-03-08 1998-08-25 Otsuka Pharmaceutical Factory, Inc. Phosphonic ester derivatives of quinazolinones
US5580979A (en) 1994-03-15 1996-12-03 Trustees Of Tufts University Phosphotyrosine peptidomimetics for inhibiting SH2 domain interactions
US5543396A (en) 1994-04-28 1996-08-06 Georgia Tech Research Corp. Proline phosphonate derivatives
US6090786A (en) 1994-06-10 2000-07-18 Fondatech Benelux N.V. Serine proteases, their activity and their synthetic inhibitors
US5601986A (en) 1994-07-14 1997-02-11 Amgen Inc. Assays and devices for the detection of extrahepatic biliary atresia
EP0702013B1 (de) 1994-09-15 2001-06-13 MERCK PATENT GmbH Imidazopyridine
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5614379A (en) 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
US6325989B1 (en) 1995-06-01 2001-12-04 Dana-Farber Cancer Institute, Inc. Form of dipeptidylpeptidase IV (CD26) found in human serum
US6265551B1 (en) 1995-06-01 2001-07-24 Dana-Farber Cancer Institute, Inc. Form of dipeptidylpeptidase IV (CD26) found in human serum, antibodies thereto, and uses thereof
EP0748800B1 (en) 1995-06-09 2001-05-09 F. Hoffmann-La Roche Ag Pyrimidinedione, pyrimidinetrione, triazinedione derivatives as alpha-1-adrenergic receptor antagonists
US5811278A (en) 1995-07-21 1998-09-22 Ajinomoto Co., Inc. Dipeptidyl peptidase IV from Xanthomonas maltophilia and process for producing the same
US6303661B1 (en) 1996-04-25 2001-10-16 Probiodrug Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals
US5965532A (en) 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6310069B1 (en) 1996-07-01 2001-10-30 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5885997A (en) 1996-07-01 1999-03-23 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US5985884A (en) 1996-07-01 1999-11-16 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US20030199672A1 (en) 1996-08-30 2003-10-23 Knudsen Liselotte Bjerre Derivatives of GLP-1 analogs
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
US6011155A (en) 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6124305A (en) 1996-11-07 2000-09-26 Novartis Ag Use of N-(substituted glycyl)-2-cyanopyrrolidines in inhibiting dipeptidyl peptidase-IV
US6156739A (en) 1997-02-01 2000-12-05 Newcastle University Ventures Limited Quinazolinone compounds
US20030060434A1 (en) 1997-02-18 2003-03-27 Loretta Nielsen Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms
US20020147130A1 (en) 1997-05-07 2002-10-10 Huber Brigitte T. Treatment of hiv
US20040171104A1 (en) 1997-05-16 2004-09-02 Novozymes Biotech, Inc. Polypeptides having dipeptidyl aminopeptidase activity and nucleic acids encoding same
US6309868B1 (en) 1997-07-05 2001-10-30 Nestec S.A. Cloning of the prolyl-dipeptidyl-peptidase from Aspergillus oryzae
US6235493B1 (en) 1997-08-06 2001-05-22 The Regents Of The University Of California Amino acid substituted-cresyl violet, synthetic fluorogenic substrates for the analysis of agents in individual in vivo cells or tissue
US6258597B1 (en) 1997-09-29 2001-07-10 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US6703238B2 (en) 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
US20040152192A1 (en) 1997-09-29 2004-08-05 Point Therapeutics, Inc. Stimulation of hematopoietic cells in vitro
US20010018210A1 (en) 1997-09-29 2001-08-30 William Bachovchin Stimulation of hematopoietic cells in vitro
US20030027282A1 (en) 1997-10-06 2003-02-06 Huber Brigitte T. Quiescent cell dipeptidyl peptidase: a novel cytoplasmic serine protease
US6485955B1 (en) 1997-10-06 2002-11-26 The Trustees Of Tufts University Quiescent cell dipeptidyl peptidase: a novel cytoplasmic serine protease
US6342611B1 (en) 1997-10-10 2002-01-29 Cytovia, Inc. Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for capsases and other enzymes and the use thereof
US6335429B1 (en) 1997-10-10 2002-01-01 Cytovia, Inc. Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof
US6214340B1 (en) 1997-11-18 2001-04-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Physiologically active substance sulphostin, process for producing the same, and use thereof
US6184020B1 (en) 1997-12-16 2001-02-06 Novo Nordisk Biotech, Inc. Polypeptides having aminopeptidase activity and nucleic acids encoding same
US6555521B2 (en) 1997-12-16 2003-04-29 Eli Lilly And Company Glucagon-like peptide-1 crystals
US20030045464A1 (en) 1997-12-16 2003-03-06 Hermeling Ronald Norbert Glucagon-like peptide-1 crystals
US6803357B1 (en) 1998-02-02 2004-10-12 New England Medical Center Hospitals, Inc. Method of regulating glucose metabolism, and reagents related thereto
US20030153509A1 (en) 1998-02-02 2003-08-14 Bachovchin William W. Method of regulating glucose metabolism, and reagents related thereto
US20020061839A1 (en) 1998-03-09 2002-05-23 Scharpe Simon Lodewijk Serine peptidase modulators
US6620910B1 (en) 1998-04-10 2003-09-16 Les Laboratoires Servier Peptide compounds analogues of the glucagon-like peptide-1 (7-37)
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US20030134802A1 (en) 1998-05-28 2003-07-17 Hans-Ulrich Demuth Novel effectors of dipepetidyl peptidase IV
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US20010020006A1 (en) 1998-06-24 2001-09-06 Hans-Ulrich Demuth Compounds of unstable DP IV-inhibitors
US20040171555A1 (en) 1998-06-24 2004-09-02 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
US20020049164A1 (en) 1998-06-24 2002-04-25 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
US6129911A (en) 1998-07-10 2000-10-10 Rhode Island Hospital, A Lifespan Partner Liver stem cell
US20020071838A1 (en) 1998-07-31 2002-06-13 Hans-Ulrich Demuth Method for raising the blood glucose level in mammals
US6319893B1 (en) 1998-07-31 2001-11-20 Probiodrug Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV
US20030176357A1 (en) 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
US20020110560A1 (en) 1998-10-06 2002-08-15 Hans-Ulrich Demuth Use of dipeptidyl peptidase IV effectors for normalizing the blood glucose level in mammals
US20020006899A1 (en) 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
US6166063A (en) 1998-12-10 2000-12-26 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6521644B1 (en) 1999-03-23 2003-02-18 Ferring Bv Compositions for promoting growth
US20030199563A1 (en) 1999-04-05 2003-10-23 Robl Jeffrey A. Heterocyclic containing biphenyl aP2 inhibitors and method
US6548529B1 (en) 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
US20030171358A1 (en) 1999-04-20 2003-09-11 Lone Jeppesen New compounds, their preparation and use
US20020049153A1 (en) 1999-05-17 2002-04-25 BRIDON Dominique P. Long lasting insulinoptropic peptides
WO2000076986A1 (de) 1999-06-10 2000-12-21 Probiodrug Gesellschaft für Arzneimittelforschung mbH Verfahren zur herstellung von thiazolidin
US20020082427A1 (en) 1999-06-10 2002-06-27 Hans-Ulrich Demuth Method for the production of thiazolidin
US6107317A (en) 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6110949A (en) 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6528486B1 (en) 1999-07-12 2003-03-04 Zealand Pharma A/S Peptide agonists of GLP-1 activity
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US20020165164A1 (en) 1999-08-24 2002-11-07 Hans-Ulrich Demuth New effectors of dipeptidyl peptidase IV for topical use
WO2001014318A2 (de) 1999-08-24 2001-03-01 Probiodrug Ag Neue effektoren der dipeptidyl peptidase iv zur topischen anwendung
US20030092630A2 (en) 1999-08-24 2003-05-15 Probiodrug Ag New effectors of dipeptidyl peptidase iv for topical use
US6559188B1 (en) 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
US20030087935A1 (en) 1999-09-22 2003-05-08 Cheng Peter T. Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6727271B2 (en) 1999-09-22 2004-04-27 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030096846A1 (en) 1999-09-22 2003-05-22 Cheng Peter T. Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2001023364A1 (en) 1999-09-28 2001-04-05 Merck Patent Gmbh Quinazolinones
US6447772B1 (en) 1999-10-01 2002-09-10 Klaire Laboratories, Inc. Compositions and methods relating to reduction of symptoms of autism
US6251391B1 (en) 1999-10-01 2001-06-26 Klaire Laboratories, Inc. Compositions containing dipepitidyl peptidase IV and tyrosinase or phenylalaninase for reducing opioid-related symptons
EP1229024A1 (en) 1999-10-08 2002-08-07 Meiji Seika Kaisha Ltd. m-SUBSTITUTED BENZOIC ACID DERIVATIVES EXHIBITING INTEGRIN ALPHA-V BETA-3 ANTAGONISM
US20010047078A1 (en) 1999-10-14 2001-11-29 Saint Louis University Methods for identifying inhibitors of methionine aminopeptidases
US6261794B1 (en) 1999-10-14 2001-07-17 Saint Louis University Methods for identifying inhibitors of methionine aminopeptidases
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
WO2001034594A1 (en) 1999-11-12 2001-05-17 Guilford Pharmaceuticals, Inc. Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
US20040152745A1 (en) 1999-11-12 2004-08-05 Guilford Pharmaceuticals, Inc. Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors
US20030096857A1 (en) 1999-11-30 2003-05-22 Evans David Michael Novel antidiabetic agents
US20030040478A1 (en) 1999-12-08 2003-02-27 Drucker Daniel J Chemotherapy treatment
US6380398B2 (en) 2000-01-04 2002-04-30 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
WO2001052825A2 (en) 2000-01-21 2001-07-26 Novartis Ag Combinations comprising dipeptidylpeptidase-iv inhibitors and antidiabetic agents
US20030139434A1 (en) 2000-01-21 2003-07-24 Bork Balkan Combinations comprising dipeptidylpeptidase-iv inhibitor
US20020103384A1 (en) 2000-01-24 2002-08-01 Anders Kanstrup Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US6645995B2 (en) 2000-01-24 2003-11-11 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20010031780A1 (en) 2000-01-24 2001-10-18 Anders Kanstrup New therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030060412A1 (en) 2000-01-27 2003-03-27 Prouty Walter Francis Process for solubilizing glucagon-like peptide 1compounds
US20030199451A1 (en) 2000-01-28 2003-10-23 Mogensen John Patrick Combination therapy using a dual PPAR-a/PPAR-y activator and a GLP-1 derivative for the treatment of metabolic syndrome and related diseases and disorders
WO2001056988A1 (fr) 2000-02-01 2001-08-09 Kirin Beer Kabushiki Kaisha Composes contenant de l'azote et possedant une activite d'inhibition des kinases, et medicaments comprenant ces composes
US6448045B1 (en) 2000-03-10 2002-09-10 The Regents Of The University Of California Inducing insulin gene expression in pancreas cells expressing recombinant PDX-1
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US20020019411A1 (en) 2000-03-10 2002-02-14 Robl Jeffrey A. Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6608038B2 (en) 2000-03-15 2003-08-19 Novartis Ag Methods and compositions for treatment of diabetes and related conditions via gene therapy
EP1136482A1 (en) 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-Amino-3-(alkyl)-pyrimidone derivatives as GSK3beta inhibitors
WO2001070729A1 (en) 2000-03-23 2001-09-27 Sanofi-Synthelabo 2-amino-3-(alkyl)-pyrimidone derivatives as gsk3.beta. inhibitors
US6555519B2 (en) 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
US20010051646A1 (en) 2000-03-31 2001-12-13 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US20030008905A1 (en) 2000-03-31 2003-01-09 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US6500804B2 (en) 2000-03-31 2002-12-31 Probiodrug Ag Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US20020198242A1 (en) 2000-03-31 2002-12-26 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US6573096B1 (en) 2000-04-01 2003-06-03 The Research Foundation At State University Of New York Compositions and methods for inhibition of cancer invasion and angiogenesis
US20020132979A1 (en) 2000-04-01 2002-09-19 Wen-Tien Chen Compositions and methods for inhibition of cancer invasion and angiogenesis
US6545170B2 (en) 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US6518277B1 (en) 2000-04-25 2003-02-11 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US20040082497A1 (en) 2000-04-26 2004-04-29 Evans David Michael Inhibitors of dipeptidyl peptidase IV
US20030216450A1 (en) 2000-04-26 2003-11-20 Evans David Michael Inhibitors of dipeptidyl peptidase IV
US20020041871A1 (en) 2000-06-01 2002-04-11 Brudnak Mark A. Genomeceutical and/or enzymatic composition and method for treating autism
US20020193390A1 (en) 2000-06-13 2002-12-19 Villhauer Edwin Bernard Pharmaceutical compositions containing an N-(substituted glycyl)-2- cyanopyrrolidine and at least one other antidiabetic agent and their use in inhibiting dipeptidyl peptidase-IV
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO2001096295A2 (en) 2000-06-13 2001-12-20 Novartis Ag 2-cyanopyrrolidine derivatives and their use as medicaments
US6620821B2 (en) 2000-06-15 2003-09-16 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US6627636B2 (en) 2000-06-15 2003-09-30 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US20030166578A1 (en) 2000-06-19 2003-09-04 Arch Jonathan Robert Sanders Combinations od dipeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabetes mellitus
WO2001097808A1 (en) 2000-06-19 2001-12-27 Smithkline Beecham Plc Combinations of depeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabete mellitus
US20040034014A1 (en) 2000-07-04 2004-02-19 Kanstrup Anders Bendtz Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
WO2002002560A2 (en) 2000-07-04 2002-01-10 Novo Nordisk A/S Purine-2,6-diones which are inhibitors of the enzyme dipeptidyl peptidase iv (dpp-iv)
US20020016100A1 (en) 2000-07-25 2002-02-07 Yazaki Coroporation Connector supporting structure
US6495544B2 (en) 2000-08-01 2002-12-17 Pharmacia Corporation Homoiminopiperidinyl hexanoic acid inhibitors of inducible nitric oxide synthase
US20030220345A1 (en) 2000-08-04 2003-11-27 Hamby James Marino 2-(4-Pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimdin-7-ones
US20040106655A1 (en) 2000-08-10 2004-06-03 Hiroshi Kitajima Proline derivatives and the use thereof as drugs
US20030166662A1 (en) 2000-08-11 2003-09-04 Pfizer Inc. Treatment of the insulin resistance syndrome
US20020037829A1 (en) 2000-08-23 2002-03-28 Aronson Peter S. Use of DPPIV inhibitors as diuretic and anti-hypertensive agents
WO2002020488A2 (en) 2000-09-06 2002-03-14 F. Hoffmann-La Roche Ag Quinoline and quinazoline derivatives as ligands for the neuropeptide y receptor
US20020082292A1 (en) 2000-09-27 2002-06-27 Sahoo Soumya P. Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
EP1197799A1 (en) 2000-09-27 2002-04-17 Fuji Photo Film Co., Ltd. Dye-forming coupler, silver halide photographic light-sensitive material, and method for producing an azomethine dye
US20040063935A1 (en) 2000-10-06 2004-04-01 Kosuke Yasuda Aliphatic nitrogenous five-membered ring compounds
US20020115843A1 (en) 2000-10-12 2002-08-22 Steve Oi Novel serine protease genes related to DPPIV
WO2002034243A2 (en) 2000-10-27 2002-05-02 Probiodrug Ag Method for the treatment of neurological and neuropsychological disorders
WO2002034242A2 (en) 2000-10-27 2002-05-02 Probiodrug Ag Method for the treatment of neurological and neuropsychological disorders
US20040053369A1 (en) 2000-10-27 2004-03-18 Abbott Catherine Anne Dipeptidyl peptidases
US20020147157A1 (en) 2000-10-30 2002-10-10 Connor Gregory S. Combination therapy comprising anti-diabetic and anticonvulsant agents
US6686337B2 (en) 2000-10-30 2004-02-03 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising anti-diabetic and anticonvulsant agents
US6586198B2 (en) 2000-10-31 2003-07-01 Vanderbilt University Method of identifying susceptibility to angiotensin converting enzyme inhibto- and vasopeptidase-inhibitor-associated angioedema
US20020103242A1 (en) 2000-10-31 2002-08-01 Sahoo Soumya P. Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
US20020164759A1 (en) 2000-11-08 2002-11-07 The University Of Georgia Research Foundation, Inc Dipeptidylpeptidases and methods of use
US20020155565A1 (en) 2000-11-10 2002-10-24 Pilar Garin-Chesa FAP-activated anti-tumor compounds
US20030055052A1 (en) 2000-11-10 2003-03-20 Stefan Peters FAP-activated anti-tumor compounds
US20040072892A1 (en) 2000-11-10 2004-04-15 Hiroshi Fukushima Cyanopyrrolidine derivatives
US20030203946A1 (en) 2000-11-17 2003-10-30 Carsten Behrens Glucagon antagonists/inverse agonists
US20020077340A1 (en) 2000-11-20 2002-06-20 Richard Sulsky Pyridone inhibitors of fatty acid binding protein and method
US20020169159A1 (en) 2000-12-11 2002-11-14 Tularik Inc. CXCR3 antagonists
US20040180925A1 (en) 2000-12-27 2004-09-16 Kenji Matsuno Dipeptidylpeptidase-IV inhibitor
US20040147434A1 (en) 2001-01-02 2004-07-29 Siegfried Ansorge Use of enzyme inhibitors of the dipeptidypeptidase iv (ec3.3.14.5) in addition to the aminopeptidase n (ec 3.4.11.2), individually or in a combination thereof, and pharmaceutical preparations thereof for the prevention and/or therapy of ischaemia-caused acute and chronic neurodegenerative process and illnesses, for example
US20040082607A1 (en) 2001-02-02 2004-04-29 Satoru Oi Fused heterocyclic compounds
US20040138148A1 (en) 2001-02-14 2004-07-15 Nobuhiko Fushimi Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof
US20020198205A1 (en) 2001-02-24 2002-12-26 Frank Himmelsbach Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20040077645A1 (en) 2001-02-24 2004-04-22 Frank Himmelsbach Xanthine derivatives,production and use thereof as medicament
US20040087587A1 (en) 2001-02-24 2004-05-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US6337069B1 (en) 2001-02-28 2002-01-08 B.M.R.A. Corporation B.V. Method of treating rhinitis or sinusitis by intranasally administering a peptidase
JP2002338466A (ja) 2001-03-15 2002-11-27 Tanabe Seiyaku Co Ltd 医薬組成物
US20040092478A1 (en) 2001-03-19 2004-05-13 Rothermel John D. Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative
US20040106656A1 (en) 2001-03-27 2004-06-03 Ashton Wallace T Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20030087950A1 (en) 2001-03-28 2003-05-08 Denanteuil Guillaume New alpha-amino acid sulphonyl compounds
US6716843B2 (en) 2001-03-28 2004-04-06 Les Laboratoires Servier Alpha-amino acid sulphonyl compounds
US20020198380A1 (en) 2001-03-30 2002-12-26 Werner Belzer Process for preparing 4,6-diaminopyrimido[5,4-d]pyrimidines
US20030119736A1 (en) 2001-04-02 2003-06-26 Hans-Ulrich Demuth Methods for improving islet signaling in diabetes mellitus and for its prevention
US20040209891A1 (en) 2001-04-11 2004-10-21 Pierre Broqua Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase IV
WO2002083109A1 (en) 2001-04-11 2002-10-24 Ferring Bv Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase iv
US6573287B2 (en) 2001-04-12 2003-06-03 Bristo-Myers Squibb Company 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
US20030103968A1 (en) 2001-04-12 2003-06-05 Andree Amelsberg Use of alpha specific antibody BIBH1 in the treatment of cancer
US20020183367A1 (en) 2001-04-12 2002-12-05 Sulsky Richard B. 2,1-Oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
US6706742B2 (en) 2001-05-15 2004-03-16 Les Laboratories Servier Alpha-amino-acid compounds
US20030060494A1 (en) 2001-05-18 2003-03-27 Nobuyuki Yasuda Pharmaceutical use of N-carbamoylazole derivatives
US20040186153A1 (en) 2001-05-18 2004-09-23 Nobuyuki Yasuda Pharmaceutical use of N-carbamoylazole derivatives
US20030092697A1 (en) 2001-05-30 2003-05-15 Cheng Peter T. Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method
US20030069234A1 (en) 2001-06-06 2003-04-10 Medina Julio C. CXCR3 antagonists
WO2003000181A2 (en) 2001-06-20 2003-01-03 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
US20040176428A1 (en) 2001-06-20 2004-09-09 Edmondson Scott D. Dipeptidyl peptidase inhibitors for the treatment of diabetes
US20040236102A1 (en) 2001-06-20 2004-11-25 Linda Brockunier Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20030135023A1 (en) 2001-06-27 2003-07-17 Hans-Ulrich Demuth Peptide structures useful for competitive modulation of dipeptidyl peptidase IV catalysis
US20030119750A1 (en) 2001-06-27 2003-06-26 Hans-Ulrich Demuth Use of dipeptidyl peptidase IV inhibitors
US20040171848A1 (en) 2001-06-27 2004-09-02 Haffner Curt Dale Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US20040242636A1 (en) 2001-06-27 2004-12-02 Haffner Curt Dale Fluoropyrrolidines as dipeptidyl peptidase inhibitors
US20040167341A1 (en) 2001-06-27 2004-08-26 Haffner Curt Dale Pyrrolidines as dipeptidyl peptidase inhibitors
WO2003002595A2 (en) 2001-06-27 2003-01-09 Probiodrug Ag Dipeptidyl peptidase iv inhibitors and their uses as anti-cancer agents
WO2003002593A2 (en) 2001-06-27 2003-01-09 Probiodrug Ag Peptide structures useful for competitive modulation of dipeptidyl peptidase iv catalysis
WO2003002596A2 (en) 2001-06-27 2003-01-09 Probiodrug Ag Use of dipeptidyl peptidase iv inhibitors as therapeutics for neurological disorders
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
WO2003072556A1 (en) 2001-06-27 2003-09-04 Prosidion Ltd. Glutaminyl based dpiv inhibitors
US20030105077A1 (en) 2001-07-03 2003-06-05 Kanstrup Anders Bendtz Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20030100563A1 (en) 2001-07-06 2003-05-29 Edmondson Scott D. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20040167133A1 (en) 2001-07-06 2004-08-26 Edmondson Scott D. Beta-amino tetrahydroimidazo (1, 2-a) pyrazines and tetrahydrotrioazolo (4,3-a) pyrazines as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2003007888A2 (en) 2001-07-20 2003-01-30 Adipogenix, Inc. Fat accumulation-modulating compounds
US6747035B2 (en) 2001-08-13 2004-06-08 Warner-Lambert Llc 1-alkyl or 1-cycloalkyltriazolo[4,3-a]quinazolin-5-ones as phosphodiesterase inhibitors
WO2003016335A2 (en) 2001-08-13 2003-02-27 Probiodrug Ag Irreversible cysteine protease inhibitors of legumain
JP2003128551A (ja) 2001-08-15 2003-05-08 Sankyo Co Ltd 新規抗糖尿病医薬組成物
WO2003022871A2 (en) 2001-09-06 2003-03-20 Probiodrug Ag Peptides having a c- terminal hydroxylamino group as inhibitors of dipeptidyl peptidase i
US20030119738A1 (en) 2001-09-06 2003-06-26 Andre Niestroj Novel inhibitors of dipeptidyl peptidase I
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
US20030186963A1 (en) 2001-09-14 2003-10-02 Dorwald Florencio Zaragoza Substituted piperidines
US20040259883A1 (en) 2001-09-14 2004-12-23 Hiroshi Sakashita Thiazolidine derivative and medicinal use thereof
US20030199528A1 (en) 2001-09-19 2003-10-23 Kanstrup Anders B. Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV
WO2003026652A1 (en) 2001-09-21 2003-04-03 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor xa inhibitors
WO2003037888A1 (en) 2001-09-21 2003-05-08 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
WO2003027080A1 (en) 2001-09-21 2003-04-03 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
US20030139429A1 (en) 2001-09-27 2003-07-24 Cohen David Saul Combinations
US20040009998A1 (en) 2001-10-01 2004-01-15 Dhar T. G. Murali Spiro-hydantoin compounds useful as anti-inflammatory agents
WO2003030946A1 (en) 2001-10-09 2003-04-17 Novartis Ag Regulation of insulin production
US20030191112A1 (en) 2001-10-12 2003-10-09 Dorwald Florencio Zaragoza Novel substituted piperidines
WO2003033524A2 (en) 2001-10-12 2003-04-24 Probiodrug Ag Peptidyl ketones as inhibitors of dpiv
US20030148961A1 (en) 2001-10-12 2003-08-07 Ulrich Heiser Peptidyl ketones as inhibitors of DPIV
WO2003035640A1 (fr) 2001-10-22 2003-05-01 Eisai Co., Ltd. Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes
US20050043299A1 (en) 2001-10-23 2005-02-24 Ferring B. V. Inhibitors of dipeptidyl peptidase iv
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US20030130281A1 (en) 2001-10-26 2003-07-10 Markus Boehringer DPP IV inhibitors
US6673815B2 (en) 2001-11-06 2004-01-06 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030130306A1 (en) 2001-11-06 2003-07-10 Pratik Devasthale Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030125304A1 (en) 2001-11-09 2003-07-03 Hans-Ulrich Demuth Substituted amino ketone compounds
US20050014946A1 (en) 2001-11-09 2005-01-20 Hans-Ulrich Demuth Substituted amino ketone compounds
WO2003040174A2 (en) 2001-11-09 2003-05-15 Probiodrug Ag Substituted amino ketone compounds
US20030089935A1 (en) 2001-11-13 2003-05-15 Macronix International Co., Ltd. Non-volatile semiconductor memory device with multi-layer gate insulating structure
WO2003045977A2 (en) 2001-11-26 2003-06-05 Trustees Of Tufts College Peptidomimetic Inhibitors of Post-Proline Cleaving Enzymes
US6664273B2 (en) 2001-11-26 2003-12-16 Schering Corporation Piperidine based MCH antagonists for treatment of obesity and CNS disorders
WO2003045228A2 (en) 2001-11-26 2003-06-05 Trustees Of Tufts College Methods for treating autoimmune disorders, and reagents related thereto
WO2003048081A2 (en) 2001-12-04 2003-06-12 Bristol-Myers Squibb Company Glycinamides as factor xa inhibitors
WO2003048158A1 (en) 2001-12-04 2003-06-12 Bristol-Myers Squibb Company Glycinamides as factor xa inhibitors
US20030166690A1 (en) 2001-12-14 2003-09-04 Soren Ebdrup Use of compounds for decreasing activity of hormone-sensitive
US20030181497A1 (en) 2001-12-21 2003-09-25 Ping Chen Heterocyclic acridone inhibitors of IMPDH enzyme
US20030171411A1 (en) 2001-12-21 2003-09-11 Kodra Janos Tibor Amide derivatives as therapeutic agents
US20030149071A1 (en) 2001-12-27 2003-08-07 Gobbi Luca Claudio Pyrido [2,1-a] isoquinoline derivatives
US20040176406A1 (en) 2001-12-27 2004-09-09 Gobbi Luca Claudio Pyrido [2,1-a] isoquinoline derivatives
US6727261B2 (en) 2001-12-27 2004-04-27 Hoffman-La Roche Inc. Pyrido[2,1-A]Isoquinoline derivatives
US20030144206A1 (en) 2001-12-29 2003-07-31 Knudsen Lotte Bjerre Combined use of a GLP-1 compound and modulator of diabetic late complications
US20030236272A1 (en) 2002-01-11 2003-12-25 Carr Richard David Method and composition for treatment of diabetes, hypertension, chronic heart failure and fluid retentive states
WO2003057200A2 (en) 2002-01-11 2003-07-17 Novo Nordisk A/S Compositions comprising inhibitors of dpp-iv and nep enzymes for the treatment of diabetes
US20030195190A1 (en) 2002-02-01 2003-10-16 Bernd Peschke Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes
WO2003063903A2 (en) 2002-02-01 2003-08-07 Probiodrug Ag Modulation of t lymphocytes using dp iv inhibitors
US6800650B2 (en) 2002-02-13 2004-10-05 Hoffmann-La Roche Inc. Pyridine and quinoline derivatives
US20030216382A1 (en) 2002-02-13 2003-11-20 Markus Boehringer Pyridine and pyrimidine derivatives
US6867205B2 (en) 2002-02-13 2005-03-15 Hoffman-La Roche Inc. Pyridine and pyrimidine derivatives
US20030195188A1 (en) 2002-02-13 2003-10-16 Markus Boehringer Pyridine and quinoline derivatives
US20030187254A1 (en) 2002-02-27 2003-10-02 Pfizer Inc. Acetyl-CoA carboxylase inhibitors
US20030162820A1 (en) 2002-02-28 2003-08-28 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US20040167191A1 (en) 2002-02-28 2004-08-26 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
WO2003076418A1 (en) 2002-03-07 2003-09-18 X-Ceptor Therapeutics, Inc. Quinazolinone modulators of nuclear receptors
US20030232761A1 (en) 2002-03-28 2003-12-18 Hinke Simon A. Novel analogues of glucose-dependent insulinotropic polypeptide
WO2003082898A2 (en) 2002-03-28 2003-10-09 Prosidion Ltd. Novel analogues of glucose-dependent insulinotropic polypeptide
US20030225102A1 (en) 2002-04-08 2003-12-04 Torrent Pharmaceuticals Ltd. Novel compounds and therapeutic uses thereof
US20040106802A1 (en) 2002-04-08 2004-06-03 Torrent Pharmaceuticals Ltd. Novel compounds and therapeutic uses thereof
WO2003092605A2 (en) 2002-04-30 2003-11-13 Trustees Of Tufts College Protease inhibitors
US20040006062A1 (en) 2002-05-06 2004-01-08 Smallheer Joanne M. Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US20040002495A1 (en) 2002-05-20 2004-01-01 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
WO2003099818A1 (en) 2002-05-23 2003-12-04 Chiron Corporation Substituted quinazolinone compounds
WO2003099279A1 (en) 2002-05-29 2003-12-04 Novartis Ag Combination of a dpp iv inhibitor and a cardiovascular compound
US20040132713A1 (en) 2002-06-04 2004-07-08 Pfizer Inc Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
US20040242898A1 (en) 2002-06-04 2004-12-02 Pfizer Inc Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
US20040002609A1 (en) 2002-06-04 2004-01-01 Pfizer Inc. Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
US6710040B1 (en) 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
US20040116328A1 (en) 2002-06-06 2004-06-17 Eisai Co., Ltd. Condensed imidazole derivatives
WO2003106416A2 (en) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Chemical process
US20040009972A1 (en) 2002-06-17 2004-01-15 Ding Charles Z. Benzodiazepine inhibitors of mitochondial F1F0 ATP hydrolase and methods of inhibiting F1F0 ATP hydrolase
US7125881B2 (en) 2002-06-24 2006-10-24 Astrazeneca Ab Use of pyrimidine—or triazine—2 carbonitiles for treating diseases associated with cysteine prostease activity and novel pyrimidine-2-carbonitile derivatives
US20040054171A1 (en) 2002-07-04 2004-03-18 Jensen Anette Frost Polymorphic forms of a 4H-thieno[3,2-E]-1,2,4-thiadiazine 1,1-dioxide derivative
WO2004017989A1 (en) 2002-08-09 2004-03-04 Prosidion Ltd. Methods for improving islet signaling in diabetes mellitus and for its prevention
US20040097510A1 (en) 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20040166125A1 (en) 2002-08-22 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
US6998502B1 (en) 2002-09-05 2006-02-14 Sabinsa Corporation Convenient process of manufacture for difluoromethylornithine and related compounds
EP1398032A1 (en) 2002-09-10 2004-03-17 PheneX Pharmaceuticals AG 4-Oxo-quinazolines as LXR nuclear receptor binding compounds
JP2004123738A (ja) 2002-09-11 2004-04-22 Takeda Chem Ind Ltd 徐放性製剤
WO2004031374A2 (en) 2002-09-18 2004-04-15 Prosidion Ltd. Secondary binding site of dipeptidyl peptidase iv (dp iv)
US20040058876A1 (en) 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
US20040259843A1 (en) 2002-09-19 2004-12-23 Madar David J. Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20040072874A1 (en) 2002-09-30 2004-04-15 Nagaaki Sato N-substituted-2-oxodihydropyridine derivatives
US20040254167A1 (en) 2002-10-18 2004-12-16 Tesfaye Biftu Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20040132732A1 (en) 2002-10-21 2004-07-08 Wei Han Quinazolinones and derivatives thereof as factor Xa inhibitors
WO2004037176A2 (en) 2002-10-21 2004-05-06 Bristol-Myers Squibb Company Quinazolinones and derivatives thereof as factor xa inhibitors
US20040259919A1 (en) 2002-10-23 2004-12-23 Magnin David R. Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods
US20040138214A1 (en) 2002-11-08 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20040110817A1 (en) 2002-11-18 2004-06-10 Pfizer Inc Dipeptidyl peptidase IV inhibiting fluorinated cyclic amides
US20040138215A1 (en) 2002-11-21 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US20050020574A1 (en) 2002-12-03 2005-01-27 Boehringer Ingelheim Pharma Gmbh Co. Kg New substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions
DE10256264A1 (de) 2002-12-03 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Imidazo-pyridinone und Imidazo-pyridazinone, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2004062613A2 (en) 2003-01-13 2004-07-29 Bristol-Myers Squibb Company Hiv integrase inhibitors
US20040198786A1 (en) 2003-02-27 2004-10-07 Aventis Pharma Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
US20050014732A1 (en) 2003-03-14 2005-01-20 Pharmacia Corporation Combination of an aldosterone receptor antagonist and an anti-diabetic agent
US20040242568A1 (en) 2003-03-25 2004-12-02 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20040242566A1 (en) 2003-03-25 2004-12-02 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20040259870A1 (en) 2003-03-25 2004-12-23 Syrrx, Inc. Dipeptidyl peptidase inhibitors
WO2004085408A1 (en) 2003-03-26 2004-10-07 Mitsubishi Pharma Corporation 2, 3, 6-trisubstituted-4-pyrimidone derivatives
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US20040229848A1 (en) 2003-05-05 2004-11-18 Hans-Ulrich Demuth Glutaminyl based DP IV-inhibitors
US20050058635A1 (en) 2003-05-05 2005-03-17 Hans-Ulrich Demuth Use of effectors of glutaminyl and glutamate cyclases
US20040254226A1 (en) 2003-05-14 2004-12-16 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050026921A1 (en) 2003-06-18 2005-02-03 Boehringer Ingelheim International Gmbh New imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US20040259902A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
US20040259903A1 (en) 2003-06-20 2004-12-23 Markus Boehringer Pyrido [2,1-a] isoquinoline derivatives
US20050032804A1 (en) 2003-06-24 2005-02-10 Cypes Stephen Howard Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
US20050038020A1 (en) 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050070531A1 (en) 2003-08-13 2005-03-31 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050070706A1 (en) 2003-08-13 2005-03-31 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050070535A1 (en) 2003-08-13 2005-03-31 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050075330A1 (en) 2003-08-13 2005-04-07 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US7470700B2 (en) 2003-08-13 2008-12-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20050065148A1 (en) 2003-08-13 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050070530A1 (en) 2003-08-13 2005-03-31 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050043292A1 (en) 2003-08-20 2005-02-24 Pfizer Inc Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors
US20050065145A1 (en) 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050065144A1 (en) 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US7304086B2 (en) 2004-02-05 2007-12-04 Probiodrug Ag Inhibitors of glutaminyl cyclase
US20080003283A1 (en) 2004-03-15 2008-01-03 Takeda Pharmaceutical Company, Inc. Dipeptidyl peptidase inhibitors
US20080108808A1 (en) 2004-03-15 2008-05-08 Jun Feng Dipeptidyl peptidase inhibitors
US20080108807A1 (en) 2004-03-15 2008-05-08 Jun Feng Dipeptidyl peptidase inhibitors
US20050261271A1 (en) 2004-03-15 2005-11-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7576076B2 (en) 2004-07-02 2009-08-18 Corcept Therapeutics, Inc. Modified pyrimidine glucocorticoid receptor modulators
US20070060528A1 (en) 2005-09-14 2007-03-15 Christopher Ronald J Administration of dipeptidyl peptidase inhibitors
US20070060530A1 (en) 2005-09-14 2007-03-15 Christopher Ronald J Administration of dipeptidyl peptidase inhibitors
US20070066635A1 (en) 2005-09-16 2007-03-22 Mark Andres Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor

Non-Patent Citations (190)

* Cited by examiner, † Cited by third party
Title
Abdel-Fattah et al. Indian Journal of Heterocyclic Chemistry (1999), 8(3), 177-182. (Abstract, 2 pages).
Abdel-Rahman, R. M.: Synthesis of some new fluorine bearing trisubstituted 3-thioxo-1, 2, 4-triazin-5-ones as potential anticancer agents: Farmaco, Edizione Scientifica, Societa Chimica Italiana, Pavia, IT, vol. 47, No. (Mar. 1992), pp. 319-326, XP008000322.
Abstract of Barnickel et al. that shows the prior art compopunds (one page).
Abstract of EP 900568 A2 from STN CAS online search printout (3 pages).
Abstract of EP 900568 that shows the prior art compounds (three pages).
Abstract of Lakhan et al. Journal of Indian Chemical Society (1987), 64 (5), 316-18 (2 pages).
Abstract of Pattanaik et al. Indian Journal of Chemistry, Section B; Organic Chemistry including Medicinal Chemistry (1998), 37B (12), 1304-1306. (three pages).
Abstract of Shyam et al. Current Science (1975), 44(16), 572-4 (one page).
Abstract of Tiwari et al. Indian of Journal of Pharmaceutical Sciences (1978), 40(2), 40-3 (2 pages).
Adel Hamid et al. Scientia Pharmaceutica (2001), 69(4), 351-366.
Akahoshi, F. et al.: "Synthesis and pharmacological activitey of triazolo[1,5-a]triazine derivatives inhibiting eosinophilia." Journal of Medicinal Chemistry, vol. 41, No. 16, (Jul. 30, 1998), pp. 2985-2993, XP002390903.
Alagarsamy, V. et al. "Synthesis and pharmacological investigation . . . " Pharmazie, vol. 57, No. 5 2002, pp. 306-307, XP008084498.
Algarsamy, V. et al. "Synthesis, analgesic, antii-inflammatory . . . " Bio & Pharm. Bulletin of Japan, Pharma society of JP, vol. 25, No. 11, 2002, pp. 1432-1435, XP008084513 ISSN: 0918-6158.
An abstract of Pattanaik et al. Indian of Chemistry, Section B; Organic Chemistry including Medicinal Chemistry (1998), 37B (12), 1304-1306 from STN CAS online search printout (3 pages).
Argaud, Doriane et al., Metaformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes, European J. Biochem. 213, 1341-1348 (1993).
Ashcroft, Stephen J.H. et al., Structure-activity relationships of alloxan-like compounds derived from uric acid, Br. J. Pharmac. (1986), 89 pp. 469-472.
Baker, B.R. et al., Irreversible Enzyme Inhibitors. On the Mode of Pyrimidine Binding of 5-alkyl and 5-Arylpyrimidines to Dihydrofolic Reductase (1,2), Journal of Heterocyclic Chemistry vol. 4 (1967) pp. 39-48.
Bal, Gunther, Dipeptidyl Peptidase IV and Prolyl Oligopeptidase: Design, Synthesis and Evaluation of Substrates and Inhibitors, (2002) Universiteit Antwerpen.
Banker, G.S. et al, "Modern Pharmaceutices, 3rd edition", Marcel Dekker, New York, 1996, pp. 451 and 596.
Barakat, S.E.S., Synthesis and hypoglycemic activity of some new 3-[4- [[[(cyclohexylamino) carbonyl] amino]sulfony]phenyl]-4(3H)-quinazolinones, Az. J. Pharm. Sci., vol. 25, (2000), pp. 48-57.
Barakat, S.E.S., Synthesis and Hypoglycemic Activity of Some New 4(3H) -Quinazolinone Analogues, Saudi Pharmaceutical Journal, vol. 8, No. 4 (2000) pp. 198-204.
Barnela et al. Indian Journal of Chemistry Section B: Organic Chemistry Including Medicinal Chemistry (1986), 25B(7), 709-11. (Abstract 2 pages).
Belgodere, Elena et al., Synthesis of Substituted Pyrimidines, Study of the Structure and of the Tautomeric Equilibria, (1976) Chem. Abstracts, Columbus, OH vol. 85 No. 9.
Bezuglyi, P.O. et al., Synthesis of arylsulfonyl hydrazide of 3-R-quinazolone-4-carbony1-2-acid, Pharmaceutical Journal (1979), pp. 70-71.
Bhaduri, A.P. et al., Urinary Metabolite of 2-Piperazino-3 (H)-4-Quinazolone (Centpiperalone), A Potent Blood Sugar Lowering Agent, Indian J. Biochem. Biophys., vol. 12 (1975), pp. 413-414.
Borrell, J. I. et al.: "Synthesis, structure and cytotoxicity evaluation of palladium(II) complexes of 4-amino-3-hydrazino-1,2,4-triazin-5(4h)-on es and 4-amino-3-(n-methylhydrazino)-1,2,4-triazi N-5(4H)-ones" Anales De Quimica, vol. 91, No. 3/4, 1995, pp. 243-252, XP008000323.
Botta, M., Saladino, R., Lamba, D. Nicoletti, R.: Researches on Antiviral Agents. 31. Synthesis and Transformations of Racemic and Chiral 6-Oxiranyl Pyrimidinones, Tetrahedron, vol. 49, 1993, pp. 6053-6070, XP002329846.
Bouras, Mohammed, et al., Metabolism of enterostatin in rat intestine, brain, membranes and serum: differential involvement of proline-specific peptidases, Peptides, vol. 16, No. 3, (1995), pp. 399-405.
Brun, Jean-Frederic, et al., Effects of Oral Zinc Gluconate on Glucose Effectiveness and Insulin Sensitivity in Humans, Biological Trace Element Research vol. 47 (1995), pp. 385-391.
Buchwald et al. "Rational Development of Practical Catalysts for Aromatic Carbon-Nitrogen Bond Formation", 1998, Accounts of Chemical Research,31, 805-818. *
Buckley, Di, Analysis of the Degradation of Insulinotropin [GLP-1 (7-37)] In Human Plasma and Production of Degradation Resistant Analogs.
Buysens, K. J. et al.: "Synthesis of New Pyrrolo[3,4-b]- and [3,4-c]pyridin(on)es and related 1,7-Naphthyridinones and 2,7-naphthyridines via intramolecular diels-alder reactions of 2(1H)-pyrazinones" Tetrahedron, Elsevier Science Publishers, Amsterdam, NL, vol. 52, No. 27, Jul. 1, 1996, pp. 9161-9178, XP004104003.
Caira M R: "Crystalline Polymorphism of Organic Compounds" Topics in Current Chemistry, Springer, Berlin, DE, vol. 198, 1998, pp. 163-208, XP001156954 ISSN: 0340-1022 p. 165.
Cecil Textbook of Medicine, edited by Bennet, J.C., and Plum F., 20th edition, vol. 1, 1004-10, 1996.
Chatterjee, A.K. et al., Effect of Centpiperalone in Insulin Deficient Diabetes, Indian Journal of Experimental Biology vol. 18 (1980), pp. 1005-1008.
Chatterjee, A.K. et al., Effect of Centpiperalone, a New Hypoglycemic Agent on Insulin Biosynthesis & Release from Isolated Pancreatic Islets of Rat, Indian Journal of Experimental Biology vol. 20 (1981) pp. 270-272.
Chenard et al. J. Med Chem. 2001, 44, 1710-1717.
Coppola, Gary M. et al., 1-Aminomethylisoquinoline-4-carboxylates as Novel Dipeptidylpeptidase IV Inhibitors, Bioorganic & Medicinal Chemistry Letters vol. 10 (2000), pp. 1555-1558.
Database Beilstein [online] Beilstein Corssfire Institut Zur Foerderung Der Chemischen Wissenschaften, DE; 1989 XP002392086.
Database Beilstein [online] Beilstein Crossfire Institut Zur Foerderung Der Chemischen Wissenschaften, DE; 1924, XP002392085.
Database Beilstein [online] Beilstein Crossfire Institut Zur Foerderung Der Chemischen Wissenschaften, DE; 1960 XP002392087. Database Accession No. BRN 609897 abstract.
Database Beilstein [online] Beilstein Crossfire Institut Zur Foerderung Der Chemischen Wissenschaften, DE; 1993 XP002392088. Database Accession No. BRN 6139401 abstract.
Database Beilstein [online] Beilstein Crossfire Institut Zur Foerderung Der Chemischen Wissenschaften, DE; Citation No. 5593678 1991, XP00239083.
Database Beilstein [online] Beilstein Crossfire Institut Zur Foererung Der Chemischen Wissenschaften DE; 1974 XP002392089. Database Accession No. BRN 514343 abstract.
Database Beilstein [online] Beilstein Crossfire Institut Zur Forderung Der Chemischen Wissenschaften, DE; 1991, XP002392082. Database Accession No. BRN 5340228 abstract.
Database Biosis [Online] Biosciences Information Service, Philadelphia, PA, US; 1991, Bahaji E-H et al.: "Studies on Immunostimulating Derivatives Synthesis of Some Pyrrolo-1 2-C-Pyrimidines" XP002392081. Database accession No. PREV19919240000 abstract.
Database CA [online] Chemical Abstract service, Columbus, Ohio, US; Reg No. 102482-94-0 Liu, Gang: "Fungal edophyte-epichloe and its secondary metabolites" XP002392084.
Database CA Online Chemical Abstracts Service, Columbus, OH, US; Troschuetz, Reinhard et al., The reaction of O-functional benzylmalononitriles with N-bisnucleophiles as well as alcoholates. XP-002311761 retrieved from STN Database accession No. 1994:217538 abstract & Archiv Der Pharmazie (Winheim, Germany), 326(11), 865-9 Coden: ARPMAS; ISSN: 0365-6233, 1993.
Database Crossfire Beilstein Institut Zur Foerderung Der Chmischen Wissenchaften, XP-002310120. Beilstein Registry Number 638238 & Synthetic Procedures in Nucleic Acid, vol. 1, 1968, p. 92.
Database Crossfire Beilstein Institut Zur Foerderung Der Chmischen Wissenschaften. XP-002310117. Beilstein Registry No. 8373244 & KHIM. Geterotsikl. Soedin., No. 8, 1998, pp. 1125-1129.
Database Crossfire Beilstein Institut Zur Foerderung Der Chmischen Wissenschaften. XP-002310118. Beilstein Registry No. 7643826 & KHIM. Geterotsikl. Soedin., vol. 32, No. 5, 1996, pp. 703-707.
Database Crossfire Beilstein Institut Zur Foerderung Der Chmischen Wissenschaften. XP-002310119. Beilstein Registry No. 649497 & J. Pharm. Sci. vol. 80, No. 7, 1991, pp. 705-706.
Database Crossfire Beilstein Institut Zur Foerderung Der Chmischen Wissenschaften. XP-002310121. Beilstein Registry No. 7289032 & Nucleosides Nucleotides, vol. 14, No. 3-5, 1995, pp. 653-656.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335064. Database Accession No. 1447881 & J. Heterocycl.Chem., vol. 305,1972, pp. 724-730.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335065. Database Accession No. 1447134 & J.Org.Chem., vol. 43, 1978, pp. 4069-4074.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335066. Database Accession No. 386682 & J.Chem.Soc., 1952, pp. 4985-4990.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335067. Database Accession No. 389575 & Chem.Ber., vol. 88, 1968, pp. 106-109.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335068. Database Accession No. 472441 &.Yakugaku Zasshi, vol. 88, 1968, pp. 106-109.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335069. Database Accession No. 1447840 & Chem.Ber., vol. 101, No. 8, 1968, pp. 2679-2689.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335070. Database Accession No. 1448669 & Chem.Ber., vol. 101, No. 8, 1968, pp. 2679-2689.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335071. Database Accession No. 4991064, J.Chem.Soc.Perkin Trans.1, 1980, pp. 1370-1380.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335072. Database Accession No. 990008, J.Prakt.Chem., vol. 315, 1973, pp. 1166-1168.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335073. Database Accession No. 6219070, J.Prakt.Chem., vol. 330, No. 2, 1988, pp. 323-324.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335074. Database Accession No. 392446, J.Heterocycl.Chem., vol. 8, 1971, pp. 367-371.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335075. Database Accession No. 4742608, J. Prakt.Chem., vol. 333, No. 1, 1991, pp. 149-151.
Database Crossfire Beilstein Institut zur Foerderung der Wissenchaften, Frankfurt am Main, DE; XP002335076. Database Accession No. 490809, & Angew.Chem., vol. 84, 1972, p. 1185.
Database Crossfire Beilstein Institut zur Foerderung der Wissenschaften, Franfurt am Main, DE: XP002335063. Database-Accession No. 1525341 & J. Heterocycl.Chem., vol. 12, 1975, pp. 683-687.
Deacon, Carolyn F. et al., Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects, Diabetes, vol. 44 (1996), pp. 1125-1131.
Deacon, Carolyn F. et al., Degradation of Glucagon-Like Peptide 1 in Vitro Yields an N-Terminally Truncated Peptide That is a Major Endogenous Metabolite in Vivo, Journal of Clinical Endocrinology and Metabolism vol. 80, No. 3 (1995), pp. 952-957.
Deacon, Carolyn F. et al., Dipeptidyl peptidase IV Inhibition as an Approach to the Treatment and Prevention of Type 2 Diabetes: a Historical Perspective, Biochemical and Biophysical Research Communications 294 (2002), pp. 1-4.
Deacon, Carolyn F. et al., Dipeptidyl peptidase IV Inhibition Influences GLP-1 Metabolism in Vivo, Regulatory Peptides vol. 64 Issues 1-3 (1996) p. 30.
Deacon, Carolyn F. et al., Dipeptidyl peptidase IV Inhibition Potentiates the Insulinotropic Effect of Glucagon-Like Peptide 1 in the Anesthetized Pig, Diabetes, vol. 47 (1998), pp. 764-769.
Demuth, Hans-Ulrich et al., Rebuttal to Deacon and Hoist: "Metaformin effects on depeptidyl peptidase IV degradation of glucagons-like peptide-1" versus "dipeptidyl peptidase inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective" Biochemical and Biophysical Research Communications 296 (2002) pp. 229-232.
Desai N C et al "Synthesis and anti-Hiv . . . " Indian Journal of Experimental Bio.,vol. 36, No. 12, 1998 pp. 1280-1283, XP008084509 ISSN: 0019-5889.
Dey, Paramita D., et al., Regioselective [4+2] Cycloaddition versus Nucleophilic Reactions of N-Arylamino Substituted 1,3-Diaza-1,3-Butadienes with Ketenes: Synthesis of Pyrimidinone and Fused Pyrimidione Derivatives. Part II. Tetrahedron, vol. 53, No. 40, pp. 13829-13840, 1997.
Dumads, Donald J. "Total synthesis of peramine" Journal of Organic Chemistry, American Chemical Society, Easton, US, vol. 5, 1988, pp. 4650-4653, XP002087391.
Engel, Michael et al., The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism, Proc. Nat. Acad. Sci. Early Edition (2003), pp. 1-6.
Fantus, I. George, et al., Mechanism of Action of Metformin: Insulin Receptor and Postreceptor Effects in Vitro and in Vivo, J. Clinical Endocrinology & Metabolism (1986), pp. 898-905.
Fraisse, L., et al. Long-Chained Substituted Uric Acid and 5,6-Diaminouracil Derivatives as Novel Agents against Free Radical Processes: Synthesis and in Vitro Activity, Journal of Medicinal Chemistry, vol. 36, 1993, pp. 1456-1473, XP002329847.
Fraser & Kermack "The Reaction of Paludrine (Proguanil) with Ethyl Acetoacetate" 1951 pp. 2682-2686.
Garratt, Peter J. et al., A Novel Synthesis of Dihydropyrimidines, J. Chem. Soc., Chem. Commun. (1987), pp. 568-569.
Garratt, Peter J. et al., One-Carbon Compounds as Synthetic Intermediates. The Synthesis of Hydropyrimidines and Hydroquinazolines by Sequential Nucleophilic Addition to Diphenyl Cyanocarbonimidate With Concomitant Cyclization, J. Org. Chem. (1988), pp. 1062-1069.
Gazit, Aviv et al., Tyrphostins IV-Highly Potent Inhibitors of EGF Receptor Kinase. Structure-Activity Relationship Study of 4- Anilidoquinazolines, Bioorganic & Medicinal Chemistry, vol. 4, No. 8 (1996) pp. 1203-1207.
Green et al., Expert Opin. Emergin Drugs, 11(3); 525-539, 2006.
Guerrieri, N., et al., Vanadium Inhibition of Serine and Cysteine Proteases, Comparative Biochemistry and Physiology Part A 122 (1997), pp. 331-336.
Gupta, A. et al.: "Fluorine containing Biologically Active Agents: Synthesis of some new Pyrimidine Derivatives" J.Ind. Chem.Soc., vol. 71 1994, pp. 635-636, XP000889664 compound 1.
Gupta, C.M. et al., A Novel Class of Hypoglycaemic Agents: Syntheses & SAR in 2-Substituted 4(3H)- Quinazolones, 2-Substituted 4-Hydroxypolymethylene 5,6] pyrimidines & 3-Substituted 4-Oxo-pyrido [I,2-a]pyrimidines, Indian Journal of Chemistry, vol. 9 (1971), pp. 201-206.
Gupta, C.M. et al., Drugs Acting on the Central Nervous System. Syntheses of Substituted Quinazolones and Quinazolines and Triazepino-and Triazocionquinazolones, Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow, India (1968), pp. 392-395.
Gupta, C.M. et al., New Potent Blood Sugar Lowering Compound, Nature, vol. 223 (1969), p. 524.
Hcaplus 121: 35089.
Hcaplus 122: 132810.
Hcaplus 1995:104821, "Cyclohedydration of 4[(carboxymethyamino}pyridin-2-ones. A new, efficient synthesis of pyrrolo [3,2-c] pyridin-4-ones and pyrido [3,4-b] pyrrolizidin-1-ones" Edstrom et al. 1994.
Hermecz, Istvan et al., Pyrido[1,2-a]Pyrimidines; New Chemical Entities in Medicinal Chemistry, Medicinal Research Reviews, vol. 8, No. 2 (1988) pp. 203-230.
Hinke, Simon A. et al., Metaformin Effects on Dipeptidylpeptidase IV Degradation of Glucagon-like Peptide-1, Biochemical and Biophysical Research Communications, 291 (2002) pp. 1302-1308.
Hinke, Simon A. et al., On Combination Therapy of Diabetes With Metaformin and Dipeptidyl Peptidase IV Inhibitors, Diabetes Care, vol. 25, No. 8 (2002) pp. 1490-1492.
Holz, George G. et al, Pancreatic Beta-Cells are Rendered Glucose-Competent by the Insulinotropic Hormone Glucaqon-Like Peptide-1(7-37), Nature, vol. 361 (1993), pp. 362-365.
Jakubkiene, Virginija, at al., (G-Methyl-2methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acid and related compounds exhibiting anti-inflammatory activity. Pharmazie 57 (2002) 9, pp. 610-613.
Jones, Terence R., et al., Azafluorenes Containing Two Bridgehead Nitrogen Atoms. Journal of the Chemical Society, Perkin Transactions 1, No. 12, Dec. 1987, pp. 2585-2592.
Kamata et al., CAPLUS Abstract 105: 191027, 1986 Chemical & Pharma Bulletin (1985), 33(8), 3160-75.
Kesarwani, A. P. at al.: Solid-phase synthesis of quinazolin-(3H)-ones with three-point diversity, Tetrahedron Letters, vol. 43, (2002) pp. 5579-5581.
Khalid, Noraini M., et al., Purification and Partial Characterization of a Prolyl-Dipeptidyl Aminopeptidase From Lactobacillus helveticus CNRZ 32, Applied and Environmental Microbiology (1990), pp. 381-388.
Kieffer, Timothy J. et al., Degradation of Glucose-Dependant Insulinotropic Polypeptide and Truncated Glucagon-Like Peptide 1 in Vitro and in Vivo by Dipeptidyl Peptidase IV, Endocrinology, vol. 136, No. 8 (1995) 3585-3596.
Kim, H.O. et al., Structure-Activity Relationships of 1,3-Dialkykanthine Derivatives at Rat A3 Adenosine Receptors, Journal of Medicinal Chemistry, vol. 37, 1994, pp. 3373-3382, XP002329848.
Kimura, Toshikiro et al., Oral Administration of Insulin as Poly(Vinyl Alcohol)-Gel Spheres in Diabetic Rats, Biological & Pharmaceutical Bulletin, vol. 19, No. 6 (1996), 897-900.
Koreeda, Yuji et al., Isolation and Characterization of Dipeptidyl Peptidase IV From Prevotella loescheii ATCC 15930, Archives of Oral Biology, 46 (2001), 759-766.
Kotani, T. et al., "Highly selective aldose reductase . . . " Journal of Medicinal Chem., American Chem. Society. Washington, US, vol. 40, No. 5, 1997, pp. 684-694 XP000652330.
Kotra, L. P. et al.: "4-Azido-2-pyrimidone Nucleosides and Related Chemistry" Journal of Organic Chemistry, American Chemical Society. Easton, US, vol. 62, 1997, pp. 7267-7271, XP002390905.
Kozhevnikov et al., Tr. Perm. Sel.-Khoz. Inst. (1971), No. 79, 66-72 From ref. Zh., Khim. 1972, Abstr. No. 9Zh404 Journal (English Abstract attached).
Kusar, Mihael et al., Diethyl N,N-Dimethylaminomethylenemalonate in the Synthesis of Fused Heterocyclic Systems, Heterocyclic Chem. 33 (1996) pp. 1041-1046.
Lambeir et al. "DPP4 from Bench to Bedside: An Update on Structural Properties, Functions, and Clinical Aspects of the Enzyme DPP4" Critical Reviews in Clinical Laboratories Sciences, 40(3):209-294 2003.
Li Jinping, et al., Permolybdate and Pertungstate—Potent Stimulators of Insulin Effects in Rat Adipocytes: Mechanism of Action, Biochemistry, 34 (1995) 6218-6225.
Lin, Jian, Total Synthesis and Biological Evaluation of Fluoroolefin-containing Dipeptidyl Isosteres as Inhibitors of Dipeptidyl Peptidase IV (CD26), Dissertation presented to State University of New York at Albany, Department of Chemistry (1998).
Loeser, Eric et al., Selective N-Alkylation of Primary Amines with Chloroacetamides Under pH-Controlled Aqueous Conditions, Synthetic Communications, 32(3) (2002) pp. 403-409.
Majim R. Berichet der Deutschen Chemischen Gesellschaft 1908 41 pp. 176-186.
Mall et al. Reactivity Difference of Cis-Trans Pairs: Different Behavior of Stillbene Oxides and Activated Stilbene Imines, 1987, Journal of Organic Chemistry, 52, 4812. *
Mall et al. Reactivity Difference of Cis-Trans Pairs: Different Behavior of Stillbene Oxides and Activates Stilbene Imines, 1987, Jornal of Organic Chemistry,52, 4812.
Malloy, J. Ardill et al., Effect of Metaformin Treatment on Gastric Acid Secretion Gastrointestinal Hormone Levels in Normal Subjects, Diabetologia, vol. 19 (1980) 93-96.
Mannucci, Eduardo, et al., Effect of Metaformin on Glucagon-Like Peptide-1 (GLP-1) and Leptin Levels in Obese Nondiabetic Subjects, Diabetes Care, vol. 24, No. 3 (2001) 489-494.
Marcus et al. PubMed Abstract (Intervirology, 45/4-6):260-6) 2002.
Mentlein, Rolf et al., Dipeptidyl-Peptidase IV Hydrolyses gastric Inhibitory Polypeptide, Glucagon-Like Peptide-1(7-36)amide, Peptide Histidine Methionine and is Respoinsible for Their Degradation in Human Serum, Eur. J. Biochem, vol. 214, 829-835 (1991).
Meyerovitch, Joseph et al., Oral Administration of Vanadate Normalizes Blood Glucose Levels in Streptozotocin-Treated Rats, The Journal of Biological Chemistry, vol. 262, No. 14 (1987) 6658-6662.
Misra, V. et al. "Synthesis of N-aryl-n . . . " Pol. J. Pharmacol Pharm vol. 31, 1979, pp. 161-167, XP008084507.
Miyamura, K. et al. "Reaction of Copper (II) Complexes Optically . . . " J. Chem. Soc. Dalton Trans. 1987, pp. 1127-1132, XP008082357.
Molina, P. et al.: "Iminophosphorane-mediated annulation of 1,3,5-triazine to benzimidazole: Synthesis of 1,3,5-triazino[1,2-a]benzimidazoles" Synthesis 1992 Germany, No. 3, 1992-pp. 297-302, XP002390907.
Mukerjee, S.S. et al., Chronic Toxicity Studies of a Hypoglycemic Compound: Centpiperalone in Rats & Rhesus Monkeys, Indian Journal of Experimental Biology, vol. 17 (1979) pp. 1346-1349.
Mukerjee, S.S. et al., Effect of 2-piperazino-4(3H)-quinazolinone monoacetate on the tissue respiration, glucose uptake and lactic acid production by rat hemidiaphragm, Biochemical Pharmacology, vol. 23 (1974) 3066-3067.
Mukerjee, S.S. et al., Studies on the Mechanism of Centpiperalone-Induced Hypoglycemia, Acta Diabet. Lat 13, 8 (1976) p. 8.
Mukerjee, S.S. et al., Tissue Distribution of [3H]Centpiperalone after Oral Administration, Indian J. Biochem. Biophys., vol. 17 (1980) pp. 399-401.
Mukherjee, Surath K. et al., A novel hypoglycemic compound, Biochemical Pharmacology, vol. 22 (1972) pp. 1529-1531.
Mukherjee, Surath K. et al., Effect of 2-piperazino-4(3H)-quinazolinone monoacetate on some aspects of carbohydrate metabolism of albino rats, Biochemical Pharmacology, vol. 22 (1973) pp. 2205-2206.
Mukherjee, Surath K. et al., Influence of Timing Oral Dosing of a Novel Hypoglycaemic Agent A-4166 in Relation to Food, Diabetologia vol. 38 A194 Supplement 1 (1995).
Mukherjee, Surath K. et al., Studies on the Metabolic Changes Induced by a Synthetic Insulinogenic Agent, Ind. J. Physiol. & Allied Sci., vol. 30, No. 3 (1976) pp. 105-116.
Mukkerjee, Sucharita "[2+2]versus [4+2] cycloaddition reactions of 1,3-diaza-1,3-butadienes with various mono and disubtituted ketenes and supporting mechanistic considerations" Heter0cycles, vol. 47, No. 2, 1998.
Murthy, G. Rama et al., New Hypoglycemic Agents: Part V—Synthesis & Hypoglycemic Activity of Some New 1-[[p-(4-OXO-2-Methyl/Phenyl-3 (4H)-Quinazolinyl) Phenyl]] 3-Aryl-2-Ureas, Indian Drugs, 25 (1) (1987) pp. 19-22.
Murthy, G. Rama et al., New Hypoglycemic Agents: Synthesis and Hypogylcemic Activity of Some New 1-[{p-(4-OXO-2-Substituted-3(4H)-Quinazolinyl)-Phenyl{Sulphonyl]-3-Aryl/Cyclohexyl-2-Thioureas, Current Science, vol. 56, No. 24 (1987) pp. 1263-1265.
Nakamura, Seiji, et al., Effect of Chronic Vanadate Administration in Partially Depancreatized Rats, Diabetes Research and Clinical Practice 27 (1995) pp. 51-59. (Abstract Only).
Noguchi, Michihiko "Generation of NH-azomethine imine intermediates through the 1,2-hydrogen shift of hydrazones and their intermolecular cycloaddition reaction with olefinic dipolarophiles" Tetrahedron vol. 59 (2003), p. 4123-3.
Ohkubo, I., et al., Dipeptidyl Peptidase IV From Porcine Seminal Plasma: Purification, Characterization, and N-Terminal Amino Acid Sequence, J. Biochem. (Tokyo) (1994) 116(5) pp. 1182-11826.
Pandeya, S.N. et al., Synthesis of Some New Amidine Derivatives As Potent Hypoglycemic Agents, Pharmacological Research Communications, vol. 17, No. 8 (1985) pp. 699-709.
Pantani et al. "Bioisosterism: A Rational Approach in Drug Design", Chem. Rev. 1996, pp. 3147-3176.
Patent Abstracts of Japan, vol. 2003, No. 12, Xanthine Derivative, Dec. 5, 2003 & JP 2003 300977 A (Sumitomo Pharmaceut Co Ltd), Oct. 21, 2003, Abstract.
Patent Asbsracts of Japan Publication No. 2002338551, Publication Date Nov. 27, 2002.
Pauly, R.P. et al., Inhibition of Dipeptydyl Peptidase IV (DPIV) in Rat Results in Improved Glucose Tolerance, Regulatory Peptides vol. 64, Issues 1-3 (1996) p. 148.
Pederson, Raymond A. et al., Improved Glucose Tolerance in Zucker Fatty Rats by Oral Administration of the Dipeptidyl Peptidase IV Inhibitor Isoleucine Thiazolide, Diabetes, vol. 47 (1998) pp. 1253-1258.
Pillai, Sreekumar et al., Effects of ATP, Vanadate, and Molybdate on Cathepsin D-catalyzed Proteolysis, The Journal of Biological Chemistry, vol. 280, No. 14 (1985) pp. 8384-8389.
Podanyi, Benjamin et al., Nitrogen Bridgehead Compounds. 62. Conformational Analysis of 6, 7, 8, 9-Tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones and Their Methyl Derivatives by NMR Spectroscopy, J. Org. Chem. 51 (1985) 394-399.
Poje, M. et al., Diabetogenic action of allozan-like derivatives of uric acid, Experentia 36 (1980) pp. 78-79.
Poje, M. et al., Oxidation of Uric Acid. 4. Synthesis, Structure, and Diabetogenic Action of 5-Imino-2,4,6 (1H,3H,5H)-pyrimidinetrione Salts and Their Alloxan-like Covalent Adducts, J. Med. Chem. 26 (1983) 861-4.
Polacek, I. et al., Hypoglycemic Activity of Amine Derivatives, Arzneim.-Forsch./ Drug Res. 28 (1978), 791-93.
Pridal, L. et al., Glucagon-Like Peptide-1(7-37) Has a Larger Volume of Distribution Than Glucagon-Like Peptide1(7-36)amide in Dogs and is Degraded More Quickly in Vitro by Dog Plasma, European Journal of Drug Metabolism and Pharmacokinetics, vol. 21 (1995), pp. 51-59.
Ram, Vishnu Ji et al., Synthesis and Antihyperglycemic Activity of Suitably Functionalized 3H-quinazolin-4-ones, Bioorganic & Medicinal Chemistry 11 (2003), pp. 2439-2444.
Rauchman, B.S. et al. "2,4—Diamino-5-benylpyrimidines and Analogues as antibacterial Agents", Journal of Med. Chem., vol. 23, 1980, pp. 384-391, XP002335048 Scheme II.
Sammour et al. Egyptian Journal of Chemistry (1979) Volume Date 1976, 19(6), 1109-16. (Abstract 2 pages).
Sawyer, James H. et al., Pyrido[1,2-a]pyrimidinium Salts. Part 1. Synthesis from 2- Aminopyridines and Interconversion with 2-(2-Acylvinylamino) pyridines, J.C.S. Perkin I (1972), 1138-1143.
Saxena, A.M. et al., Mode of action of three structurally different hypoglycemic agents: A comparative study, Indian Journal of Experimental Biology, vol. 34 (1996), pp. 351-355.
Schilling et al., CAPLUS 2005:1050865 DN 143:347172.
Sederaviciute et al., CAPLUS Abstract 125:300937 (1996).
Sedo, Aleksi et al., Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities? Biochimica et Biophysica Acta 1550 (2001), pp. 107-116.
Sekiya, T. et al., Pyrimidine derivatives. III (1) Synthesis of hypoglycemic 4-alkoxy-2-piperazino-activity of 6-polymethylenepyrmidines, Eur. J. Med. Chem. (1982), 75-79.
Senten, Kristel et al., Development of Potent and Selective Dipeptidyl Peptidase II Inhibitors, Bioorganic & Medicinal Chemistry Letters 12 (2002) pp. 2825-2828.
Seth, M. et al., Syntheses of 2-Substituted & 2,3-Distributed 4(3H)-Quinazolones, Indian Journal of Chemistry, vol. 14B (1975), 536-540.
Sharma, Arun K., et al. Tandem sigmatropic shifts in [4 +2] cycloaddition reactions of 1,3-diazabuta-1,3-dienes with butadienylketene: synthesis of pyrimidinone derivatives. J. Chem. Soc., Perkin Trans. 1, 2002, 774-784.
Shimazawa, Rumiko et al., Novel Small Molecule Nonpeptide Aminopeptidase N Inhibitors with A Cyclic Imide Skeleton, J. Enzyme Inhibition, vol. 14 (1999) pp. 259-275.
Shisheva, Assia, et al., Insulinlike Effects of Zinc Ion in Vitro and in Vivo; Preferential Effects on Desensitized Adipocytes and Induction of Normoglycemia in Streptozocin-Induced Rats, Diabetes, vol. 41 (1992), pp. 982-988.
Sinyak, R. S. et al., Synthesis and Biological Properties of Derivatives of 4-Heterylmercaptoquinazoline, Translated from Khimiko-farmatsevlicheskii Zhumal, vol. 20, No. 2, pp. 168-171 (1986), pp. 103-105.
Sokal, Joseph E., Basal Plasma Glucagon Levels of Man, Journal of Clinical Investigation, vol. 46, No. 5 (1967) pp. 778-785.
Soliman et al. Journal of the Chemical Society of Pakistan (1986), 8(2), 97-106. (Abstract 2 pages).
Somasekhara et al. Indian Journal of Pharmacey (1972), 34(5), 121-2.
Somasekhara et al. Indian Journal of Pharmacy (1972), 34(5), 121-2.
Srivastava, P.P. et al., Efficacy of Centpiperalone in Combination With Biguanide & Sulfonylurea, Indian Journal of Experimental Biology, vol. 21 (1983), pp. 390-392.
STN Printout, Barnickel et al. Abstract of WO 01/23364 A1.
Sun et al. CAPLUS Abstract 128:257413 (1998).
Tam, S. Y-K, et al.: "Nucleosides 112. Synthesis of Some New Pyrazolo-1 5-A-1 3 5-Triazines and Their C Nucleosides" Journal of Organic Chemistry, vol. 44, No. 25, 1979, pp. 4547-4553, XP002390906.
Tanaka, Keiji et al, Vanadate Inhibits the ATP-Dependant Degradation of Proteins in Reticulocytes Without Affecting Ubiquitin Conjugation, The Journal of Biological Chemistry, vol. 259, No. 4 (1983), 2803-2809.
Van Heeswijk et al., PubMed Abstract (Antivir Ther. 6(4);2001-29) Dec. 2001.
Villhauer, Edwin B. et al., 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties, J. Med. Chem. 46 (2003), pp. 2774-2789.
Villhauer, Edwin B. et al., DPP-IV Inhibition and Therapeutic Potential, Annual Reports in Chemistry 36 (2001), 191-200.
Vippagunta et al, Advanced Drug Delivery Reviews 48: 3-26, 2001.
Wang et al. "Studies of Quinazolinones . . . " Biorganic & Med hem . . . Letters, Oxford, GB, vol. 12, No. 4, 2002, pp. 571-574, XP009077496 ISSN 0960-894X.
Wang, F. et al.: "A novel Synthesis of Aryl[1,2-a]pyrazine Derivatives" Molecules, Molecular Diversity Preservation International, Basel, CH, vol. 9, May 2004, pp. 574-582, XP002390904.
Weber, A.E.: Dipeptidyl Peptidase IV Inhibitors for the Treatment of Diabetes, Journal of Medicinal Chemistry, vol. 47, 2004 pp. 4135-4141, XP002329845.
Wells, Carol L. et al., Role of Anaerobic Flora in the Translocation of Aerobic and Facultatively Anaerobic Intestinal Bacterial, Infection and Immunity, vol. 55, No. 11 (1987) pp. 2689-2694.
West, Antony R., Solid State Chemistry and its Applictions, Wile, New York, 1988, pp. 358 & 365.
Wiedeman, Paul E. et al., Dipeptidyl peptidase IVinhibitors for the treatment of impaired glucose tolerance and type 2 diabetes, Current Opinion in Investigational Drugs, vol. 4, No. 4 (2003), pp. 412-420.
Wolf et al., CAPLUS Abstract 115: 114452 (1991).
Wolf Manfred E. "Burger's Medicinal Chemistry, 5ed, Part 1" John Wiley and Sons, 1995, pp. 975-977.
Yasuda, Nobuyuki et al. Enhanced Secretion of Glucagon-Like Peptide 1 by Biguanide Compounds, Biochemical and Biophysical Research Communications 298 (2002), pp. 779-784.
Yuen, V.G. et al., Acute and Chronic Oral Administration of Bis(maltolato)oxovanadium(IV) in Zucker Diabetic Fatty (ZDF) Rats, Diabetes Research and Clinical Practice 43 (1999), pp. 9-19.
Zander, Mette, et al., Additive Glucose-Lowering Effects of Glucagon-Like Peptide-1 and Metformin in Type 2 Diabetes, Diabetes Care, vol. 24, No. 4 (2001) pp. 720-725.
Zhang, Anqi et al., Vanadate Stimulation of Insulin Release in Normal Mouse Islets, The Journal of Biological Chemistry, vol. 266, No. 32 (1991), pp. 21649-56.

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